Natural Cures For Prostate Cancer

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Prostate Reconstitution Models

Prostate is another tissue in which reconstitution has been successfully established. The prostate develops from the embryonic urogenital sinus (UGS), which is composed of urogenital sinus epithelium (UGE) and urogenital sinus mesenchyme (UGM). When implanted under kidney capsule, dissociated UGS cells or the mixture of UGE and UGM cells can develop into prostate tissue with normal morphogenesis and functional differentiation (39). If the UGS cells are infected with retroviruses carrying v-Ha-ras and or Myc prior to implantation, carcinomas develop from the reconstituted prostate (40). The reconstitution system also allows the opportunity to explore the interaction between epithelium and stroma during tumorigenesis (41,42). BPH-1 is an immortalized but non-tumorigenic human prostatic epithelium cell line. When mixed with rat UGM, benign, but nontumorigenic, growth developed in the reconstituted prostate. However, if the host mice were treated with testosterone plus estradiol (T+E2),...

Prostate Cancer an Overview30

In the Curative Treatment of Prostate Cancer Prostate cancer accounts for 21 of all neoplasms in the male population in Germany (Schussler et al. 1993) and has similar rates of incidence in most countries in the Western world. This cancer type has long been mentally connected with old men's diseases, and the level of commitment to research aimed at the development of new diagnostic and therapeutic approaches to it has therefore been relatively low. Now, however, with increasing survival rates even in older age groups, interest in improving its diagnosis and treatment is growing. With new trends in N-stag-ing (see Wawroschek et al. 1999, 2000) in mind, it will be much more difficult to develop convincing strategies for detection of sentinel lymph node(s) (SLN), and it is also more difficult to dissect them, whether in isolation or together with secondary nodes within the pelvis, in the course of prostate cancer treatment than in the procedures used in breast cancer or malignant...

Importance of Tumor Volume to Clinical Significance in Treatment of Prostate Cancer

Stamey et al. (1993) tried to calculate the probability of having a diagnosis of prostate cancer within a man's life. The prostates of 139 consecutive bladder cancer patients who had undergone cystopros-tatectomy were examined. Prostate cancer was found in 55 patients (40 ), larger cancers being detected only in 8 . The cancers ranged in volume from 0.5 to 6.1 ml. These results allowed the conclusion that prostate cancers smaller than 0.5 ml

Gleason Score Grading in Ultrasoundguided Biopsies Related to Results in Prostatectomy Specimens

In their comparative studies of ultrasound-guided biopsies and prostatectomy specimens conducted in 289 cases, Gregori et al. (2001) obtained the following results summarized in Tables 3 and 4. It is very interesting that with whole-prostate evaluation (specimen investigations) as reference, upstaging is necessary in about 40 , that among cases with unilateral positive biopsies bilateral cancer infiltration is found in about 65 , and that among cases with bilateral positive biopsies intra-capsular cancer infiltration is found in about 66 .

Intraoperative and Postoperative Lymph Node Staging in the Treatment of Prostate Cancer

However, we should always keep in mind that the quantity of tissue lost is much greater in frozen sections than in paraffin embedding and paraffin sectioning. Therefore, when two-step surgery is planned (node evaluation and prostatectomy) basing a decision for prostatectomy exclusively on frozen sections of the lymph nodes is of restricted value. As in staging procedures used for other cancers see Chapter on Melanoma (Chapter 25) , Okegawa et al. (2000) also performed RT-PCR studies of the dissected lymph nodes for staging prostate cancer by preliminary investigations, to detect early lymph node metastases, and to define the indications for prostatectomy more precisely. Positive results were obtained in 11 of stage pT2a and in 25 of stage pT2b cases. Invasion of prostate cancer into seminal vesicles did not significantly alter the frequency of involved nodes (61 versus 70 ), as published by Barzell et al. (1977).

Wawroscheks Vogts and Harzmanns First Approach to Detection of Sentinel Nodes in Prostate Cancer

Following on from these open questions, Harzmann and his group performed a pilot project with injection of 2 ml of mTc containing contrast solution transrectally into the body of the prostate gland. They then faded out the central prostatic region and looked for the localization of the SLNs by scintigraphic investigations. With this method they were able to detect the positions of SLNs outside of the iliac and obturator regions, which are Wawroschek's, Vogt's and Harzmann's First Approach to Detection of Sentinel Nodes in Prostate Cancer 471 Harzmann's group followed the principle of performing total-body bone and CT scans, investigating the acid phosphatase and prostate-specific antigen levels, and also performing transrectal ultrasonography, all preoperatively. After these, mTc nanocolloid (Nanocoll, Sorin, Italy) was injected into the prostate, one or two injections being given into each prostate lobe. When this procedure was followed the total activity reached 100 MBq with a...

Is Fdgpet Helpful in Detection and Nstaging of Prostate Cancer

Various studies have shown that FDG is not suitable for diagnosing changes in the prostate gland, as prostate cancer is often not accompanied by an increase in glucose metabolism. In a study of primary prostate cancer, Effert et al. (1996) noted only low metabolic activity in most tumors, which was not related to tumor grade or stage. Data from 11 patients with localized prostate cancer and 2 with benign prostate hyperplasia confirmed these results (Hofer et al. 1999). Following radical prostatectomy and an increase in prostate-specific antigen (PSA), it is not possible to differentiate between scar tissue and local recurrence by means of FDG-PET. Of 6 patients with a local recurrence diagnosed by biopsy, 5 had false-negative results in the PET scan (Hasemann et al. 1996). At the same time, 2 out of 4 patients with negative biopsies showed enhanced FDG-uptake. Therefore, metabolic activity of local recurrences following radical prostatectomy cannot be distinguished from vascularized...

Role of folate hydrolase in prostate cancer

Folic acid is integral to the various metabolic processes within the body involving one-carbon transfers in DNA synthesis, DNA methylation, and formation of methionine which when decarboxylated is used in polyamine synthesis (74,75). Our initial thinking was that PSM', the alternative spliced form of PSMA, might put the prostate at risk of folate deficiency because as a folate hydrolase, it would allow for deglutamation of the poly-y-glu-tamated folates, which are the intracellular storage form of folates. Given that PSM' is less glycosylated being an intracellular protein, we now consider it likely that PSM' does not have folate hydrolase activity. At present, the probable function of the intracellular form PSM' is not known. Outside of the cell, PSMA does bind and hydrolyze poly-y-glutamated folate. However, serum contains folate in a form that is not poly-y-glutamated and is ready for transport into tissues. In the normal prostate, PSMA is at the apical surface it is possible that...

Suitability Of Prostate Cancer As Target For mAbBased Therapy

Prostate cancer is ideally suited as a target for mAb-based therapy for several reasons (5) (1) Organ- or tissue-specific antigens of this nonessential organ, rather than cancer-specific antigens, can be targeted (2) bone marrow and lymph nodes, the most frequent sites of prostate cancer metastases, have been demonstrated to be responsive to mAb therapies in other tumor types (3) prostate cancer is relatively radiosensitive and is, therefore, likely to be a good target for radionuclide-bearing mAbs (4) the typically small volume of prostate cancer metastases allow ready antibody penetration and access to antigen (5) relapse and or metastatic disease is readily detected early by using the serum PSA assay before clinical manifestations become evident and while tumors are still small and can be readily targeted by mAbs (6) patients at high risk can be predicted by clinically validated measures before PSA failure, and mAb therapy can be initiated in these patients while the tumor burden...

Prostatespecific Membrane Antigen

Just as prostate cancer seems to be an ideal target for mAb therapy in general, prostate-specific membrane antigen (PSMA), the most well-studied, highly restricted prostate cell surface antigen (6-11), seems to be an ideal specific cellular target because it is expressed by all prostate cancers (8,9,12-14). It is an integral type II cell surface transmembrane glycoprotein (Fig. 1) (15,16), and its level of expression is increased with increased tumor dedifferentiation (9,13,17), and in metastatic and hormone-refractory cancers (8,9,13,14, 17,18). In addition to expression by prostate cells, it can be expressed also by nonprostate tissues such as small intestine, proximal renal tubules, and salivary glands (10), albeit at levels 100- to 1000-fold less than in prostate tissue (11). PSMA expression was also found on the vascular endothelium of solid tumors and sarcomas, but not of normal tissues (8, 10,13,17-22). PSMA, therefore, represents a potential target for antiangiogenic...

Therapy Regimens for Prostate Cancer

The standard therapy for prostate cancer is medical ablative hormone therapy with GnRH analogues. Additional antiandrogenic therapy is recommended before the start of medication, as there may be a transitory increase in testosterone levels (flare-up) at the beginning of medication (orchi-ectomy is an alternative, but is usually not the therapy of first choice, for psychological reasons). Therapy can be given in 3-month or in 1-month cycles (Table 49).

Serum psa cutoff in diagnosis of prostate cancer

Even though serum PSA levels increase in men with cancer of the prostate, PSA is not recommended as the only screening procedure for the diagnosis of cancer, because elevated PSA levels also are observed in patients with BPH. DeAntoni et al. showed that 90 of healthy men volunteers in the United States had serum PSA < 4 pg L (70 had < 2 pg L) (23). Of the 10 of that population with PSA > 4 pg L, about one-third would have CaP if the prostate is systematically biopsied (24). Of all CaP detected among patients tested, > 75 are now impalpable, organ-confined tumors with good prospect for cure (25). Accordingly, 4 pg L has been the most accepted cutoff in screening for CaP today. However, this cutoff does produce a low specificity (i.e., high false positive), necessitating many unnecessary biopsies, resulting in increased morbidity and cost. Various attempts have been made to improve this cutoff. For example, depending on the age and extent of the symptoms, from 21 (26) to 86 (27)...

Psma expression in prostate benign prostate hyperplasia and prostate cancer

Prostate Cancer Number Scale

Prostate-specific membrane antigen has been detected in both benign tissue and prostate cancer and is clinically designated as prostate-specific (2). In the past, various methods have been employed to distinguish BPH from among various grades of prostate cancer. By employing in situ hybridization, Kawakami et al. (51) increased expression of PSMA-specific transcripts in poorly differentiated adenocarcinoma in 15 tumors (from a range of Gleason scores). Similarly, by employing immunohistochemistry analysis with PSMA-specific antibody, Burger et al. (52) confirmed that PSMA expression reflects the Gleason score of the tumor with PSMA expression localized in secretary epithelial cells. Bostwick et al. (53) has shown intense cytoplasmic immune reactivity for PSMA in every prostate tissue examined. The number of immune-reactive cells increased incrementally from benign epithelium to high-grade prostatic intraepithelial neoplasia (PIN) and prostatic adenocarci- noma. The most extensive and...

Clinical Trials Of Prostate Cancer Using HuJ591

Prostate Cancer represents an excellent target, especially for monoclonal antibody-based therapy for the following reasons (64) 1. The prostate is a nonessential organ and its destruction will not harm the host, and the identification of tissue-specific antigens for antibody development is easier than elusive tumor-specific antigens. 2. The sites of prostate metastasis being lymph nodes and bone are sites that receive high levels of circulating antibodies. 3. Metastases are typically of small volume, allowing ready access to therapy, and are identified early following primary therapy by elevation in serum prostate-specific antigen (PSA). 5. Monoclonal antibodies (mAbs) can mediate antitumor effect by targeting radionuclides, and prostate cancer is relatively radiosensitive. The tissue-specific protein PSMA is an excellent target for imaging and therapy because it is a cell surface protein that presents a large extracellular target and it is expressed at levels that are about a...

By Utilizing Both the EST Database and the Human Genome Sequence

In this approach, we identify EST clusters that are breast-specific or prostate cancer-specific, as described in the previous approach, and then align the assembled cluster sequence into the human genome using the Golden Path human genome browser (http genome.ucsc.edu). We then analyze a region about 180 kb in size around the locus of the identified genomic sequences for genes predicted to encode membrane proteins using different gene-prediction programs. After the identification of the candidate genes, we experimentally validate the finding as described earlier and then isolate a full-length cDNA and obtain its sequence and that of the predicted protein. Two new members of the ABC transporter superfamily have been identified using this approach, one of which is a potential target for immuno-based therapy of breast cancer.

Identification of Genes Encoding Membrane Proteins by Generating a Membrane Associated Polyribosomal cDNA Library

Unlike for prostate cancer, the EST mining approach did not identify many breast cancer candidate genes. Taking advantage of the fact that there are many breast cancer cell lines that accurately reflect the properties of the parental cancer (which is not the case with prostate cancer), we decided to use breast cancer cell lines to search for new membrane-associated proteins. Our strategy was to isolate membrane-associated polysomal RNA from several phenotypically diverse breast cancer cell lines with different properties such as ER positive, ER negative, erbB2 positive, and erbB2 negative. This RNA, which is enriched in transcripts encoding membrane and secreted proteins, was then used to generate a large high-quality cDNA library with an average insert size of 2 kb. We call this library MAPcL (Membrane Associated Polyribosomal cDNA Library). Sequencing of900 clones confirmed that the library was greatly enriched for the desired mRNAs. The cDNA library was then subtracted with RNA...

Proteomics for Cancer Diagnosis Cancer Recurrence Prediction and Personalized Cancer Therapy Monitoring

Early diagnosis of ovarian cancer has been shown to yield cure rates of 95 , whereas late-stage discovery results in a cure rate of only 35 (94,95). A novel biomarker for early diagnosis of ovarian cancer is critical because the conventional biomarker CA-125 is relatively insensitive for early-stage detection of ovarian cancer (96). Using mass-spec-trometry-based proteomics approach, Petricoin et al. has achieved a breakthrough in identifying distinctive serum protein pattern fingerprints to discriminate ovarian cancer patient from normal with 100 sensitivity and 95 specificity, which was improved to 100 sensitivity and 100 specificity, respectively, by a more sophisticated bioinfor-matic approach (27,97). This result showed the emergence of an accurate yet cost-effective, real-time, noninvasiveness proteomic method for early-stage detection of ovarian cancer. Similar proteomic techniques have also been developed for other cancers, including prostate, breast, lung, and colon cancers...

Target identification

Bcl-2 belongs to a growing family of proteins that regulates programmed cell death (apoptosis). Overexpression of Bcl-2 has been observed in breast cancer, prostate cancer, B-cell lymphomas, colorectal adenocarcinomas, and many other forms of cancer. Therefore, Bcl-2 is an attractive anticancer target. Discovery of novel classes of small-molecule inhibitors targeted at the BH3-binding pocket in Bcl-2 has been reported (20). The 3D structure of Bcl-2 has been modeled on the basis of a high-resolution NMR solution structure of Bcl-X(L), which shares a high sequence homology with Bcl-2. A structure-based computer screening approach was been employed to search the National Cancer Institute 3D database of organic compounds. The results suggest that the structure-based computer screening strategy employed in the study is effective for identifying novel, structurally diverse, nonpeptide small-molecule inhibitors that target the BH3 binding site of Bcl-2.

New strategies for discovery of accessible tumor targets

One widely used approach to reducing sample complexity has been to study tumor cells that have been isolated and grown in culture. Unfortunately, both enzymatic mechanical tissue disassembly and growth in culture contribute to phenotypic changes that alter native cellular function and protein expression (36). Direct comparisons of protein expression have revealed < 25 similarity between primary tumor cell biopsies vs cultured, clonally selected prostate tumor cell lines vs patient-matched microdissected cell-populations-derived biopsy specimens (37). For example, in vitro caveolin-1 expression is downregulated in transformed cell lines and in various cultured human cancer cell lines, and induced expression greatly retards tumor cell growth (38-44). Yet, in vivo, caveolin-1 can be highly expressed in tumors and is associated with increased tumor cell survival, aggressiveness, metastatic potential, suppression of apoptosis, acquisition of multidrug resistance, and resistance to...

Targeting transcription factors to enhance chemotherapy sensitivity

Highly attractive targets for drug design are the transcription factors, which are upreg-ulated in a large variety of human cancers. In addition, there are only a few transcription factors reported (compared to the number of oncogenes, for example) (69). The potential advantages of targeting a transcription factor in cancer cells are as follows (1) A variety of dysregulated signal transduction pathways might be effected by targeting a single transcription factor and (2) targeted therapy effective in one form of malignancy might be equally effective in many types of malignancy. There are three major groups of transcription factors the steroid receptors, the resident nuclear proteins, and the latent cytoplasmic factors (70). Exemplified in the steroid receptor group, one finds the estrogen receptors in breast cancer and the androgen receptors in prostate cancer. Drugs targeting

The AKT Signaling Pathway

Growth factors, oncogenic Ras, and integrins could activate this survival pathway. Once activated, the phosphatidylinositol-3 kinase (PI3K) facilitates the conversion of PIP2 to PIP3, which then activates the transcription factor AKT. This has been shown to promote transcription of antiapoptotic Bcl-XL and inactivate Bad, caspase-9 and FKHRL1 (an inducer ofmany proapoptotic factors) (83). A tumor suppressor, phosphatase and ten-sin homolog (PTEN), is regulatory and counteracts AKT by phosphorylating PIP3. AKT is constitutively activated in a wide range of tumors such as prostate, liver, lung, ovary, and breast carcinomas (84). Also, this pathway has been observed to cause resistance to chemotherapy one example is inhibition of cisplatin-induced apoptosis in ovarian carcinoma through phosphorylation ofthe proapoptotic Bad. Treatment with either the AKT inhibitor wortmannin or exogenous expression of a dominant-negative AKT sensitized the cells to cisplatin (85). Another successful...

TNF Receptors and Trail Apo2L

Recombinant human TRAIL (10 mg kg administered once daily for 7 d) (97). One of the most exciting features of TRAIL therapy is the strong positive interaction effect of TRAIL with chemotherapeutic agents or ionizing radiation. TRAIL treatment has been shown to sensitize tumor cells derived from acute leukemia, breast cancer, lung cancer, colon cancer, prostate cancer, and melanoma to chemotherapeutic agents (98-105). In an in vitro setting, TRAIL has been shown to induce apoptosis in normal primary hepatocytes (106). In light of this observation, it remains to be seen whether TRAIL therapy offers a margin of safety in humans, as is seen in mice and monkeys.

Modeling Tumorigenesis in Transgenic Mice

The most straightforward construct used to generate transgenic mice consists of a promoter enhancer element driving the expression of a gene of interest. Some promoters enhancers can lead to ubiquitous expression (e.g., the -actin or PGKpromoters). However, using a tissue- or cell-type-specific promoter permits restriction of the expression of the gene of interest to a tissue type in which the gene is known or suspected to be involved in transformation. Examples include MMTVLTR for mammary gland specific expression (9), CCSP promoter for lung-specific expression (10), rat Probasin promoter for prostate-specific expression (11) and K14 promoter for epithelial-cell-specific expression (12). The gene of interest might be a viral oncogene (e.g., SV40 large Tantigen and polyoma middle T pyMT ) (8) or a cellular component involved in cell survival and proliferation, such as MYC, members of the RAS family, and various growth factors and their receptors. For instance, a transgenic mammary...

Reconstitution models

Transgenic and knockout technologies are powerful tools in generating tumor models. However, both systems have their limitations. Tissue reconstitution is another method to generate primary tumors in mice. Tissue reconstitution has been developed to recapitulate the events leading to cancer development in adult mice. The concept is to reconstitute a tissue from genetically modified cells, thereby allowing the opportunity to study the tumorigenic effects of genetic factors and hormonal factors from various components of the tissue. This approach has been best illustrated by the reconstitution of mammary and prostate glands.

Xenograft Models Using Cultured Tumor Cells Constitutively Expressing Luciferase

Many cultured tumor cell lines have been transfected to express luciferase constitu-tively, including mouse colon adenocarcinoma line MC38 and human prostate PC-3M C6 and human colon HT-29 D6. These luc-labeled cultured tumor cells have been used in models of tumorigenesis that have increased sensitivity over conventional models and allow for longitudinal study design. Imaging the same group of mice over time also permits the kinetics of drug efficacy to be monitored over time with increased statistical significance (9,14,15).

SiRNA Transgenic Systems and Viral Based Delivery

The next steps using siRNA approaches will involve producing conditional mice where spatial and temporal control of siRNA expression is achieved. Human prostate carcinoma cells (PC-3) were engineered to contain a Tet-inducible siRNA for either the p110a or p110P subunits of phosphatidylinositol 3-kinase (PI-3 kinase) (76). Inhibition of PI-3 kinase was tested and confirmed in vitro. The siRNA containing PC-3 cells were injected into the left dorsolateral prostate gland of male nude mice to develop an orthoptopic prostate tumor metatasis model. Doxycycline (Dox) was administered in the drinking water for 56 d postimplant. Prostate tumors, local and distant metastases, were evaluated. Mice with the p110P siRNA induced by Dox for 56 d showed a significant decrease in lymph node metastases even though the prostate tumor size in siRNA-treated and mice controls was similar. Results with the p110a siRNA showed no observable reduction in tumor metastases from controls. The existence of siRNA...

PDGFR Signaling and Tumorigenesis

Signaling through the PDGF-D P PDGFR complex might occur in a paracrine, juxta-crine, or autocrine manner depending on the coexpression of PDGF-D and P PDGFR on cancer cells. Autocrine PDGF expression induces PDGFR autophosphorylation on tyrosine residues, which creates the sites for physical interactions, with a number of proteins activating intracellular signaling pathways that are critical for oncogenic transformation, including cell proliferation and survival. P PDGFR tyrosine phosphorylation was observed in neuroblastoma-derived cells (T98G) and to a lesser extent in SK-N-AS cells by anti-phosphotyrosine immunoblots of cell lysates immunoprecipitated with a P PDGFR-spe-cific antibody (9). Autophosphorylation of human glioma cell lines (A172, U87, U251) and a rat glioma cell line (C6) was also reported (9,20). Recently, Ustach et al. (10) reported that prostate carcinoma cells (LNCaP) autoactivated latent PDGF-D into the active PDGF domain, which can induce phosphorylation of P...

PDGFD Induces Morphological Transformation In Vitro and Tumor Formation In Vivo

When injected subcutaneously into nude mice, and the growth of the tumor could be inhibited by a small molecule piperazinyl quinazoline kinase inhibitor (CT52923) that is highly selective for PDGFR and c-kit. To determine if ectopic PDGFD expression induced cell transformation, NIH-3T3 transfectants were generated by various groups (8,9). pMT-PDGFD was engineered to express the proteolytically processed and thus activated PDGF-D p35. NIH-3T3-PDGFD transfectants exhibited foci of morphologically transformed cells characterized by a dense, disorganized pattern of growth, comprised of individual cells found to be spindly in shape with increased refractility, whereas NIH-3T3 cells transfected with control pMT vector retained a normal morphology. Furthermore, potent P PDGFR tyrosine phosphorylation was detected in NIH-3T3-PDGFD transfectants. Li et al. (8) also reported that PDGF-D is a potent transforming growth factor for NIH-3T3 cells, causing increased cell proliferation and anchorage...

Inhibition of PDGFR for Cancer Therapy

Numerous studies have demonstrated the expression of a PDGFRs and ( PDGFRs in glioblastomas. Immunohistochemical analysis showed that approx 80 of prostate tumor tissues express PDGFRs at both primary and metastatic sites (33). Interestingly, ( PDGFR staining is more prominent in endothelial cells following exposure to prostate tumor cells that express PDGF (34), suggesting PDGF signaling for prostate cancer progression in a paracrine manner. The PDGFR inhibitor STI 571, in combination with paclitaxel, was shown to substantially reduce prostate cancer bone metastasis in a mouse model (34). PDGF effects on tumor interstitial pressure and drug delivery have also been documented. Whether STI 571 acts through the blockade of the PDGF-D ( PDGFR pathway or another PDGF PDGFR pathway requires further investigation.

Tumor Suppressor Genes Mimic Methylation Patterns in Different Tumor Types

With the progression of the disease, a large number of cancer genes have been reported to carry high level of methylation in a normally unmethylated promoter (33-40) for example, RASSF1,RARbeta,DAPK,p16,p15,MGMT, and GSTP1 in lung cancer, CDKN2A, CALCA, MGMT, and TIMP3p in esophageal cancer, 14ARF in ulcerative colitis, GSTP1 in prostate cancer, HIC-1 and p53 in breast cancer. It is not yet established whether methylation is an initiating event or a secondary event in gene silencing. Irrespective of the role of methylation in the initiation of tumor development, methylation both marks and plays a key role in an epigenetically mediated loss of gene function that is as critical for tumori-genesis as mutations in coding regions. Prostate

Cell cycle and proliferation markers

It has been determined that specific cell cycle regulators are associated with adverse outcome in prostate cancer (9). Through the G1- to S-phase transition of the cell cycle, cyclin D1 is a critical modulator of progression and frequently overexpressed in malignancies. Cyclin D1 was shown to play a role in both breast and prostate tumorigenesis by mediating hormone receptor signaling (9) and its overexpression is linked to the subsequent development of distant metastasis in prostate cancers (10). The Cip Kip and INK4 groups of cyclin-dependent kinase inhibitors have been found to be of prognostic value in prostate cancer (9,11,12,75-77). Loss ofp27expression has been linked with adverse disease outcome in a number of studies (9,11,12). Overexpression of p34cdc2 cyclin-depen- For cell proliferation markers, immunohistochemical analysis using MIB-1 Ki-67 antibody has become the standard for quantifying cell cycle progression in human tissues (14, 15), where, generally, > 16-20 MIB-1...

HER2 Oncoprotein Overexpression

ERBB-2 or HER-2 neu, a member of the tyrosine kinase family, has been well studied in breast cancer (88-91). Recent studies demonstrated poorer survival and response rates to specific chemotherapeutic agents in those patients whose primary breast tumors overexpress HER-2 neu (91). It has been also shown that low HER-2 neu gene expression was associated with a better response to therapy (57). This conclusion has led to the clinical testing of HER-2 as a useful standard of practice status for guiding treatment of breast cancer. For prostate cancer, previous studies also found that overexpression of HER-2 was associated with an adverse outcome (9,35,56,58,59). For example, HER-2 mRNA levels have been correlated with metastatic disease and androgen-independent hormone refractory progressive disease (92). In a recent study, the prognostic relevance of HER-2 protein expression in patients undergoing curative radiotherapy (RT) was compared to the traditional prognostic factors such as...

EBAG9RCAS1 Expression

EBAG9, estrogen receptor-binding fragment-associated gene 9, has been identified as a primary estrogen-responsive gene from MCF-7 human breast cancer cells (70). EBAG9 is identical to the receptor-binding cancer antigen expressed on SiSo cells (RCAS1), which has been reported as a cancer cell surface antigen implicated in immune escape (71). Taka-hashi and his colleagues have just examined EBAG9 expression in human prostatic tissues using normal prostatic epithelial cells and PC-3, DU145, and LNCaP cancer cells by Western blot analysis and explored its prognostic value in patients with prostatic cancer (72). EBAG9 was much more profusely expressed in the prostate cancer cells than the normal epithelial cells, which correlated well with advanced pathologic stages and high Gleason score. Positive EBAG9 immunoreactivity significantly correlated with poor PSA failure-free survival. Immunodetection of EBAG9 RCAS1 expression can be a negative prognostic indicator for patients with prostatic...

Molecular biology of kgf 21 Expression and Regulation

The mechanism of induction of KGF could be via cytokines known to regulate KGF expression Interleukin-1 (IL-1) has been shown to strongly induce the expression of KGF mRNA and protein in fibroblasts from multiple sources, whereas platelet-derived growth factor-BB (PDGF-BB), IL-6, and transforming growth factor-a (TGF-a) have also been shown to produce moderate induction (22,23). Glucocorticoids such as dexamethasone have been demonstrated to inhibit KGF expression (24-26), whereas nonsteroidal anti-inflammatory agents had no effect on KGF production. KGF has been proposed as a primary mediator of steroid hormone action in organs in the male and female reproductive tracts, including the prostate, seminal vesicle, and endometrium (27-31). This is because testosterone stimulates KGF expression in prostate stromal cells (27,28). Similarly, estrogen induces KGF expression in mammary stromal cells (29), endometrial epithelial cells (30), and isolated thecal cells from bovine ovarian...

Reduced Antigen Presentation by Tumor Cells

Because tumor-specific cytotoxic T lymphocytes (CTL) recognize tumor antigen associated with MHC class I molecules expressed on the tumor surface, any alteration in the tumor antigen processing and presentation will greatly affect CTL immunity. In fact, downregulation or complete loss of MHC I molecules have been demonstrated in a wide array of tumors, particularly prostate, colon, lung, and breast cancers (5-12). Disruption or downregulation of antigen processing components, such as TAP (transporters associated with antigen processing) and LMP (components of the proteasome complex) genes have also been observed in several tumor types, including breast, prostate, and renal cancers (13-15). Another tactic tumors exploit is downregulation or alteration of tumor antigens. Several independent research groups described the loss of melanoma-associated antigen either during treatment by adoptive transfer of ex vivo expanded antigen-specific CTL (16) or during immune therapy by tumor...

Phase i clinical trials in solid tumors

Recently, results of a phase I trial by Aghajanian et al. have been published. In this study, 43 patients in a variety of neoplasms were treated with single-agent bortezomib in doses ranging from 0.13 to 1.56 mg m2 dose. The tumor types included were non-small-cell lung cancer (NSCLC), colon, head and neck, melanoma, ovary, renal, prostate, bladder, cervix, endometrial, esophagus, gastric, and unknown primary. A total of 89 doses were administered, with an average of 2 cycles per patient. The median number of previous chemotherapeutic regimens was four. Reported DLTs were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. One partial response was seen in a patient with NSCLC. The maximum tolerated dose (MTD) was established at 1.56 mg m2. Pharmacodynamics studies showed a dose-related inhibition of 20S proteasome activity with increasing dose of...

RANKL and Its Receptors

Therapeutic inhibition of the RANKL pathway by soluble OPG receptor or by blocking antibodies to RANKL or RANK was recently examined in murine models of human multiple myeloma and prostate carcinoma (123,175). In both examples, soluble RANK or OPG prevented bone destruction and metastasis. Collectively, these data suggest that OPG, soluble RANK, or an anti-RANKL RANK blocking antibodies might be of therapeutic value for patients with multiple myeloma and metastatic bony tumors. Tumor cells that express RANK might also be targeted anti-RANK antibody, similar to anti-CD20 antibody therapy of NHL. This approach could be tested in Hodgkin's disease, whereas RANK expression is restricted to the malignant Reed-Sternberg cells (112).

TRAIL and Its Receptors

The preferential activity of TRAIL against cancer cells has generated hopes for its potential use in cancer therapy (2,176,177). In fact, TRAIL has some antitumor activity against the majority of human cancer cell lines,including those derived from colon, lung, breast, kidney, prostate, brain, pancreas, skin, lymphoma, myeloma, and leukemia (2). TRAIL activity is independent of p53 status, which makes it potentially effective against tumors that are resistant to chemotherapy (178). Recently, the use of an anti-TRAIL-Rl or TRAIL-R2 monoclonal antibody was found to be as effective as TRAIL in killing tumor cells, and it was not toxic to normal human hepatocytes (179,180). Furthermore, the activity of TRAIL and anti-TRAIL-Rl or anti-TRAIL-R2 was enhanced by chemotherapy or radiation therapy in vitro and in vivo (181). Clinical trials using anti-TRAIL-Rl and anti-TRAIL-R2 are ongoing in patients with multiple myeloma and solid tumors. These important trials will provide valuable...

Insulin Like Growth Factor I Receptor

(IGF-II 2- to 15-fold lower affinity). Signaling mediated by the IGF-IR has been reported to result in neoplastic transformation, tumor cell growth, survival, angiogenesis, and metastasis (117-119). Parallel to the findings obtained in cellular settings and in vivo animal models (120), a substantial number of clinical studies also support an important role for this receptor in human cancer. Increased expression of IGF-IR, IGF-I, or both has been documented in carcinomas of the lung, breast, thyroid, colon, and prostate (121), and although contradictory among some studies, it is generally accepted that increased risk of solid tumors is associated with high levels of IGF-1 in plasma (122-124).

Cancer And The mTor Pathway

Pathways upstream of mTOR are activated in many human cancers. The dual-function phosphatase that negatively regulates PI3K, PTEN, is mutated, silenced, or deleted in a number of tumor types, including glioblastoma, hepatocellular carcinoma, lung carcinoma, melanoma, endometrial carcinomas, and prostate cancer (95-97). The net effect of loss of function is an upregulation or constitutive activation of AKT and, consequently, mTOR signaling. Mutation and activation of AKT2 or gene amplification occurs frequently. Similarly, mutations in TSC proteins, associated with the tuberous sclerosis syndrome, are associated not only with well-vascularized hamartomas (benign lesions) but also with an increased risk of renal cell carcinoma. Mutations in the LKB1 kinase gene are associated with the Peutz-Jehgers cancer prone syndrome. LKB1 kinase positively regulates AMPK, an activator of TSC2 function. Cancer-related changes in pathways downstream of mTOR are also reported. S6K is overexpressed or...

Inhibitors of mTOR Results from Preclinical Models

Since the original identification of the tumor suppressing properties of rapamycin in the NCI cancer screen, rapamycin, and, later, the analogs CCI-779 and RAD001 have been tested for their effects on a number of tumor-derived cell lines and mouse xenograft tumor models (107-109). Treatment of rapamycin or its analogs inhibits proliferation in a large number of cell lines, and in some instances treatment leads to apoptosis. These cell lines are derived from a number of tumor types, including rhabdomyosarcoma, neuroblastoma, glioblastoma, small-cell lung carcinoma, osteosarcoma, pancreatic carcinoma, renal cell carcinoma, Ewing's sarcoma, prostate cancer, and breast cancer (110-125). The breadth of tumor types that are affected is impressive but not surprising given the role of mTOR as a nutrient sensor, cell cycle regulator, and growth regulator, all of which are important for tumor progression. However, the results also provide a cautionary note, because for most of the tumor types,...

Psmafolh1NAALADaseGCPII

Prostate-specific membrane antigen (PSMA) has an important role in prostate carcinogenesis and progression, glutamatergic neurotransmission, and folate absorption (1). Each of these different areas of research activity leads to different names being given to PSMA. Because of its strong expression in the prostate (where its function is unknown), it is named as PSMA in the central nervous system, where it metabolizes the brain neurotransmitter, A-acetyl-aspartyl-glutamate, it is named NAALADase in the proximal small intestine, its role is to remove y-linked glutamates from poly-y-glutamated folate, folate hydrolase (FOLH1) and as a carboxypeptidase, glutamate carboxypeptidase II (GCPII). Our focus in this chapter will be on its biology and role in the prostate and prostate cancer. PSMA is upregulated many-fold in prostate cancers (PCAs), metastatic disease, and hormone-refractory PCAs. PSMA expression is modulated inversely by androgen levels (2,3). Most interestingly, PSMA expression...

PSMA Discovery and Mapping

Prostate-specific membrane antigen is a type II membrane glycoprotein, Mr 100,000 Dalton with an intracellular segment (amino acids 1-18), a transmembrane domain (amino acids 19-43) and an extensive extracellular domain (amino acids 44-750) (Fig. 1A). The human PSMA gene was first cloned in Heston's laboratory from lymph node metastatic lesion of adenocarcinoma of prostate (LNCaP) cells (2) and was found to be located in chromosome 11p11-12, which encodes for PSMA transcript expression in the prostate (68). Another gene highly homologous to PSMA was found to be located at the loci 11q14.3 and is called PSM-like. The PSM-like gene is expressed in different tissues, such as the kidney and liver, but not in the prostate (9)

Relative Amounts of Psmapsm in Different Tissues

Expression of PSMA and its splice variant PSM' in primary tissues has been analyzed by a number of semiquantitative techniques, including immunohistochemistry, Western blotting, and in situ hybridization with specific RNA probes (10). In their studies, Su et al. have shown that PSMA PSM' expression is highly indicative of disease progression. In primary prostate tumors, PSMA was found to be a dominant transcript, whereas normal and BPH tissues express more PSM' than PSMA. In normal tissues, PSMA PSM'-speci-fic transcripts were found to be restricted to basal epithelium, with very weak background expression in stromal cells.

Gene Therapy Using PSMA Enhancer

Prostate-specific membrane antigen is tissue-specific that is, PSMA promoter could drive the expression of the luciferase reporter gene specifically in prostate cancer cell lines LNCaP and C4-2, but not other nonprostate cell lines such as breast cancer (MCF-7), lung cancer (H157) and colorectal cancer (HCT8) cell lines in vitro. Expression of suicide gene cytosine deaminase (CD) under the control of the PSMA promoter-enhancer in prostate cancer cells sensitized the cells to 5-fluorocytosine (5-FC) with the inhibitory concentration (IC50) < 300 imol L in vitro. Furthermore, in vivo studies with athymic nude mice carrying transfected to C4-2 cells with the same therapeutic construct (used in in vitro studies) carrying CD gene under regulatory control of the PSMA promoter-enhancer could efficiently sensitize the cells to 5-FC (intraperitoneal injection of 5-FC, 600 mg kg twice a day for 3 wk). All C4-2 cell tumors expressing the therapeutic construct were killed by 5-FC, showing in...

In Combination With Low Dose Interleukin2

Patients received daily a low-dose subcutaneous rIL-2 (1.2 106 IU mL daily) continuously beginning on d 1. Following 3 wk of IL-2, patients received 25 mg m2 HuJ591 for 3 consecutive weeks. IL-2 was continued for 2 additional weeks for a total of 8 wk (one cycle). Patients who responded to therapy or had stable disease were eligible for additional cycles of therapy. Two studies indicated that weekly-administered HuJ591 was well tolerated, specifically targeted prostate cancer, and appeared to result in PSA stabilization in some patients.

Clinical Trials of the Solid Tumor Malignancies

This study is based on the fact that PSMA is expressed in the neovasculature of numerous solid tumors. However, PSMA is not expressed by normal vascular endothelium in benign tissues or neoplastic epithelial cells of nonprostate malignancies. It has been demonstrated by immunohistochemistry using CD34 immunostaining, by RT-PCR, and by in situ hybridization, showing mRNA transcripts for PSMA in multiple nonprostate solid tumor malignancies. A phase I dose escalation trial of mI-labeled mAb HuJ591 was initiated (73) and patients entering the study had a variety of solid tumors, including renal, bladder, colon, pancreatic, breast, and lung. Patients with these tumors were similar to those with prostate cancer in that they tolerated mAb HuJ591 well, with no development of HAHA.

Ligands and receptors of the tnf superfamily

TRAIL was identified through searches of expressed sequence tag (EST) databases for sequences containing homology to FasL and TNF-a (23,24). TRAIL is a type II membrane protein that is cleaved by an extracellular cysteine protease releasing the soluble ligand in a homotrimeric subunit structure (25-27). Despite the readily detectable presence of TRAIL mRNA in many normal human tissues and cells, including prostate, lung, lymphocytes, and spleen, expression of membrane-bound TRAIL is restricted to a narrow population of immune cells. Cell surface expression of TRAIL has been detected in interleukin (IL)-15- or IL-2-activated NK cells, virally infected T-cells, interferon-activated monocytes and dendritic cells, as well as CD3+ T-cells and can confer tumoricidal activity to monocytes and NK cells (28-36). The soluble and membrane-bound form of TRAIL induced apoptosis in a wide variety of human tumor cells both in vitro and in vivo without affecting the viability of normal cells...

Endocytic Function of PSMA

Psma Internalization

Prostate-specific membrane antigen, like other cell surface receptors, undergoes inter-nalization constitutively, and such spontaneous internalization is enhanced threefold in a dose-dependent manner by PSMA-specific monoclonal antibody J591 (32). It has been shown very clearly biochemically (by using biotinylated cell surface PSMA followed by internalization of the protein), by immunofluorescence analysis or immunoelecton microscopy, that PSMA or the PSMA-antibody complex undergoes internalization through cla-thrin-coated pits and closely resembles the internalization pathway of transferrin receptor and finally ends up in the lysosomes. Such constitutive internalization of PSMA might reflect the recycling of a structural protein or be mediated by binding of a ligand. A detailed characterization of antibody-mediated PSMA internalization revealed the resemblance with the epidermal growth factor receptor (EGFR) with its ligand (33). It is well known that many ligands and their...

Arnab Chakravarti MD and Gary Guotang Zhai PhD

Prostate cancer is responsible for 3 of all deaths in the Western world in men over 55 yr of age. An urgent yet challenging priority in cancer biology is to detect or identify the sequential genetic and epigenetic events early enough through characterizing cancer-associated genes and their protein products. At a specific stage, biomarkers reflect the physiologic state of a cell and might be vital for the identification of early cancer and subjects at risk of developing cancer. Biomarkers have become an important diagnostic tool in prostate cancer. With the advent and recent successes in functional genomics and proteomics, we are experiencing growing interest in discovering more molecular-based prognostic factors that could be utilized to assay the original needle biopsy specimen to tailor the primary treatment for individual prostate cancer patients. As targeted therapy in oncology becomes increasingly powerful, there is a significant interest in finding prognostic markers in prostate...

Ca2Selective Cation Channel TRPV6

The epithelial Ca2+ cation channel TRP family members have been shown to exhibit cellular homeostatic and regulatory functions. Alterations in their expression might be associated with malignant growth. The gene of the Ca2+-selective cation channel CaT-L or TRPV6 is not expressed in benign prostate tissues, including benign prostate hyperplasia, but is upregulated in prostate cancer (68). Fixemer et al. reported very recently on the differential expression of TRPV6 mRNA in prostate tissue obtained from 140 patients with prostate cancer (69). They showed, via in situ hybridization, that TRPV6 transcripts were undetectable in benign prostate tissue, high-grade prostatic intraepithelial neoplasia, incidental adenocarcinoma, and all tumors less than 2.3 cm3. Their data demonstrated that TRPV6 expression, as a plasma membrane Ca2+ channel, has a direct relationship with prostate cancer progression, thus representing a prognostic marker and a promising target for new therapeutic...

Pradip Datta PhD DABCC

Serum PSA Cutoff in Diagnosis of Prostate Cancer Methods for Measuring Serum PSA Significant improvement in prostate cancer diagnosis and monitoring of therapy has been made possible by the discovery and use of prostate-specific antigen (PSA) measurement in patient serum. Widespread use of the PSA test has resulted in significant prevention of death from this major cancer disease in males. PSA measurements are used not only to stage the patient's cancer or monitor therapy but also to screen for patients who need the prostate biopsy, a costly and painful process. There are controversies present with regard to the serum PSA cutoff (4.0 g mL), above which level the cancer is suspected. A lower cutoff (2.5 g mL) improves sensitivity of cancer detection but reduces the specificity, because benign diseases of the prostate also might raise serum PSA. Measurement of serum PSA isoforms complex or free PSA has been reported to improve the efficiency of the PSA test. The main way serum PSA is...

Apoptosis Markers bcl2 bax AND bclx

Suppression of overexpression of apoptosis genes or downregulation of proapopto-tic genes can promote radioresistant phenotypes. For instance, the protein product of the bcl-2 oncogene enhances cell survival by suppressing apoptosis (26). bax, a related homolog of the bcl-2 protein, can form heterodimers with bcl-2 and, therefore, antagonize its function and promote apoptosis (27,102). Therefore, the combination of overexpression of bcl-2 and low expression of bax are hypothetically associated with decreased apoptotic response to radiation and increased radiation resistance. On the contrary, increased bax and low bcl-2 should dictate increased apoptotic response and higher sensitivity to radiation. Recent studies in bcl-2 family proteins have established the connection of the overexpression of the antiapoptosis protein bcl-2 with decreased expression of the proapop-totic protein bax and adverse outcome in prostate cancer associated with resistance to cytotoxic chemotherapy in patients...

Regulation of PSMA Expression by PSMA Promoter Enhancer

Prostate-specific membrane antigen has been shown to be increased severalfold in the expression in prostate cancer its expression is suppressed by androgen. Currently, two regulatory elements controlling PSMA expression have been characterized. The proximal Fig. 5. The regulation of PSMA in prostate cancer cells. Negative regulation by androgen receptor and positive regulation by Ca2+ is shown. Polyglutamated folates become enzymatically cleaved to deglu-tamated folates and glutamates. The folates can enter the cells through reduced folate-carrier (RFC) or folate-binding proteins (FBP). The glutamates produced by the PSMA-expressing cells can activate metabotrophic glutamate receptors, which can become activated and alter the resting membrane potential, which causes the efflux of Cl- ions and influx of Ca2+ ions to compensate for the damage of the cells. Ca2+ ions can modulate the expression level of PSMA in many ways. Increased Ca2+ concentration can activate inactive transcription...

Clinical Development of Panitumumab

A multicenter phase I clinical trial was conducted in patients with EGFR-positive cancers to evaluate the safety, pharmacokinetics, and clinical effect of panitumumab. This was a monotherapy, open-label, and dose-escalating clinical trial in patients with late-stage renal cell, prostate, non-small-cell lung, pancreatic, colorectal, or gastroesophageal cancers, who had relapsed or progressed on standard antitumor therapy for their malignancy. All patients were prescreened for EGFR expression in their tumor tissues using immunohistochemistry. The EGFR detection in tumor tissues had to display the following staining characteristics 2+ or 3+ in 10 of evaluated tumor cells. A central laboratory using a validated EGFR immunohistochemistry kit developed by DAKO Cytomation Corporation determined the levels of EGFR expression in patient tumor samples. At an interim analysis, 43 patients were enrolled in this phase I trial with cancer types including renal (n 10), prostate (n 13),...

Preclinical Development of Panitumumab

Panitumumab has been evaluated in an extensive series of in vitro assays and in vivo human tumor xenograft models. Panitumumab causes cell cycle arrest at the G0 G1 interphase in vitro and inhibits tumor colony formation (40). Upon binding to the receptor, panitumumab is rapidly internalized, resulting in a marked downregulation of cell surface EGFR in A431 cells (40,41). When the effect on EGFR signaling was evaluated, panitumumab was found to inhibit EGF-induced EGFR tyrosine phosphorylation. Panitumumab also inhibited proliferation of A431 cells and of the breast cancer cell line MDA-468 in vitro (26). The fact that no exogenous EGF was added to the culture suggests that panitumumab blocks autocrine growth stimulation and thus inhibits EGF TGF-a-mediated tumor activation and proliferation. Interestingly, treatment of the prostate cancer cell line DU145 with panitumumab in vitro resulted in inhibition of VEGF and interleukin-8 production, suggesting that the antitumor activity of...

Tapan K Bera PhD Kristi A Egland PhD B K Lee PhD and Ira Pastan MD

Completion of the human genome sequence has opened up an enormous opportunity to researchers all over the world. The Human Genome Project, which includes the expressed sequence tags (EsTs) database and the genome sequence database, provides a huge source of data that can be used to study and identify molecular targets for a wide range of diseases, including cancer. Major efforts must now be devoted to develop strategies by which these databases will be mined efficiently to identify the hidden therapeutic treasures. We have utilized the EST and genome databases, different bioinforma-tics tools, and several experimental methods to identify tissue-specific genes for prostate and breast cancer. The genes identified can be used as novel targets for the diagnosis and treatment of prostate and breast cancer.

Arundhati Ghosh PhD and Warren D W Heston PhD

PSMA Expression in Prostate, Benign Prostate Hyperplasia, and Prostate Cancer Regulation of PSMA Expression and Its Implication in Prostate Cancer Clinical Trials of Prostate Cancer Using HuJ591 Role of Folate Hydrolase in Prostate Cancer References Prostate-specific membrane antigen (PSMA) is a novel marker that represents an excellent ideal cell-surface-bound protein for targeted therapy of prostate cancer and vas-culotoxic therapy of nonprostate solid cancers. Clinical trials using humanized version of PSMA-specific antibodies that target the external domain of PSMA with imaging or toxic agents have been encouraging. PSMA is expressed in the prostate and is found to be strongly upregulated in prostate cancer and it is the second highest upregulated gene in Gleason grade 4 5 prostate cancer compared to benign prostate hyperplasia. PSMA is negatively regulated by androgen and the PSMA promoter-enhancer has been analyzed in detail and has been used in gene therapy for selective...

Gene Identification by EST Database Mining

The Cancer Genome Anatomy Project (CGAP) of the NCI along with other consortiums support sequencing of ESTs from many cancers and their corresponding normal tissues (www.cgap.nci.nih.gov). We use this information to search for new genes and the proteins they encode (7). We search the human EST database (which now contains the sequences of over 5 million ESTs) for DNA sequences that have the following properties (1) expressed in prostate cancers or breast cancers, (2) not associated with known genes, and (3) not expressed in any essential organ or tissue. These sequences are arranged into clusters based on sequence identity (Fig. 1A see Color Plate 1 following p. 78) and a consensus sequence is produced. A typical EST cluster is shown in Fig. 1B. New Genes Discovered in Prostate and Breast Cancer Abbreviations PR, prostate TE, testis PL, placenta BR, breast N.D., not determined. Fig. 1. Schematics showing ESTs and EST clusters. (A) Schematic description of ESTs from different tissue...

Clinical trial results with avastin 21 Efficacy

Avastin as a single agent has shown encouraging results in renal cancer as a second-line therapy. A recently published report comparing two doses of Avastin (3 mg kg and 10 mg kg q 2 wk) with placebo for second-line therapy of renal cancer patients that had failed IL-2 therapy showed clinical benefit of the higher dose (11). This trial was stopped early when the 10-mg dose revealed a statistically significant prolongation of time to progression from 2.5 mo in the placebo arm to 4.8 mo (p < 0.5). This high-dose arm also showed a 10 response rate versus 0 in the other arms. Although there was no increase in survival, this trial allowed crossover to Avastin in patients who progressed on placebo. Other phase II trials evaluating Avastin with chemotherapy (pancreas, prostate) have been undertaken with very early promising results (12). Results of Avastin in trials of other tumor types are too early to report.

Psa forms in serum measurement of free or complexed psa

Prostate-specific antigen exists predominantly in circulation as complexes with various protease inhibitors such as arantichymotrypsin (ACT), a2-macroglobulin, and other acute-phase proteins (48). However, complexing with the macroglobulin enfolds the PSA entity totally, resulting in the antigenic loss of PSA in those complexes (49). Thus, the most prevalent form of complexed PSA (cPSA) found in CaP patient sera is the ACT complex (ACT-PSA) (50). Overall in all patient samples, ACT-PSA contributes 60-95 , free PSA contributes 5-40 , and other PSA complexes contributes 1-2.5 toward the total serum PSA measured. The relative proportion of the cPSA increases in CaP and decreases in benign prostatic diseases (50). Because the concentration of PSA in serum, even when elevated, is much less (100-1000 times) than the concentration of ACT, it is reasonable to conclude that the PSA isoforms in CaP or BPH could be different, the latter less able to bind ACT than the former. It has been proposed...

Pros and Cons of Reconstitution Models

There are several advantages to reconstitution models. (1) In the reconstituted tissue, the oncogene expressing cells proliferate in a mixture with normal cells, which mimics tumor growth in humans. (2) The reconstitution procedure itself restricts expression of oncogenes to specific cell types. Therefore, any ubiquitous promoter can be used to drive the expression of the oncogenes, whereas tissue-specific promoters are needed in establishing transgenic models. (3) The stroma environment can be modified by choosing specific mouse strains as recipient mice. (4) Early or mild lesions can be observed and propagated through reconstitution. (5) Mammary or prostate glands can be rescued from mutant mice with a lethal phenotype. (For example, Brca2ASH ASH mutant mice start to die at around birth, yet, the MECs of those mice can be collected from E15.5 embryos and used in reconstitution.) (6) This system allows the implantation ofdonor cells into isogenic hosts, thereby retaining the dynamic...

Inhibitors of mTOR Clinical Trials

Based on the preclinical data, a phase I trial evaluating the safety of CCI-779 was implemented (126). The results indicate that with daily intravenous treatment, there are significant grade 3 toxicities, including hypocalcemia, vomiting, thrombocytopenia, and increase in the level of hepatic transaminase. One patient had an objective response (non-small-cell carcinoma), and a number of patients had minor responses or stable disease (cervical carcinoma, uterine carcinoma, renal cell carcinoma, and soft tissue sarcoma). On a weekly treatment schedule, patients experienced no grade 3 toxicities regardless of dosage. Three patients had a partial tumor regression (renal cell, neuroendocrine, and breast carcinomas). Subsequently, based on the phase I results, phase II trials were initiated to study the effects treating advanced-stage refractory renal cell carcinoma with CCI-779 (127,128). The results of the two completed trials were positive, with an objective response rate of 5-7 , a...

Novel therapeutics targeting the trail cell death pathway

The potency of the ligand TRAIL on human tumor cells has been demonstrated primarily in human cell lines in vitro and in xenograft models and primary tissues transplanted into immunocomprimised mice. TRAIL, either alone or in combination with chemo-therapeutic agents, has demonstrated in vitro efficacy against cell lines derived from a broad array of human tumors, including those derived from the colon, brain, uterus, ovary, liver, breast, prostate, kidney, lung, thyroid, leukemic, lymphoma, and myeloma lineages (6,12,23,56,80,83,86,88-99). This broad and potent spectrum of activity against many different types of human cancer cell lines suggests that this agent might be effective across a wide range of human cancers. Of significance, TRAIL treatment of chemoresistant or radioresistant tumor cell lines enhances the cytotoxic effect of chemotherapy, including adriamycin-resistant myeloma, radioresistant lymphoma, and taxane- and platinum-insensitive breast and osteosarcoma cell lines...

Targets of the proteasome

Cyclin-dependent protein kinase inhibitors (CKIs) p21WAF1 CIP1 and p27KIP1 are also degraded through the UPP (13,14). CKIs form a complex with cyclin-cdk, inhibiting its activity and thus inducing G1 S cell cycle arrest (15). In fact, low expression ofp27KIP1 has been shown to be associated with tumor aggressiveness and poor prognosis in various neoplasms, including breast (16), colon (17), prostate (18), and non-small-cell lung cancer (19).

Unique Enzymatic Functions of PSMA

Prostate-specific membrane antigen is a protein with two unique enzymatic functions, including NAALADase activity (cleaving terminal glutamate from the neuro-dipeptide, N-acetyl-aspartyl- glutamate NAAG and folate hydrolase activity, which cleaves the terminal glutamates from y -linked polyglutamates. NAAG is concentrated in neuronal synapses, whereas folyl-poly-y-glutamates are present in dietary components and PSMA protein on the surface of the brush border epithelium of the small intestine enables the generation of folates and subsequent folate uptake. Thus, the question that comes into one's mind is what is a protein like PSMA with such interesting activity profile doing on the surface of prostate cells and why is its expression level enhanced so many-fold in prostate cancer cells The answer is still unknown, but there are several possible explanations, which we will discuss in this chapter. The structural similarities between PSMA and other proteins are known. The PSMA gene is...

Strategies

Several experimental methods have been used to identify genes that are selectively expressed in a particular cancer. These include differential display (2), subtractive hybridization (3), serial analysis of gene expression (4), and microarray analysis (5). The publication of the human genome sequence has provided a new era for cancer research (6). Using bioinformatics as a tool to mine the expressed sequence tags (ESTs) and human genome sequence databases, one can identify new genes that can serve either as targets for cancer therapy or improve our understanding of the essential biological pathways that control cell growth, differentiation, or transformation of normal cells into cancer cells. Our laboratory is particularly interested in discovering genes that can be used as targets for the therapy or diagnosis of prostate and breast cancer. We have employed three strategies to identify genes that are specifically expressed in prostate and breast cancers but not in any essential normal...

Discussion

Our effort to identify new molecular targets for the treatment of breast and prostate cancer has produced many promising candidates. Our strategy of identifying new genes is not as time-consuming as the conventional approaches. In addition to identifying several therapeutically important targets, we also identified several noncoding prostate- and breast-specific genes, which could have regulatory roles in gene expression. The overall success rate of identifying tissue-specific targets from the computer-generated cluster was about 20 , that is, only about 20 of the candidates identified by EST database screening are prostate or breast cancer-specific. We believe that is the result of the incompleteness of the EST database.

Tree interpretation

First, we note that nodes 5 and 6 are either purely or predominately cancer. However, these two nodes have different profiles, particularly in terms of CANX. In the existing literature, the expression of the molecular chaperone CANX was found to be decreased in HT-29 human colon adenocarcinoma cells (29) and to be involved in apoptosis in human prostate epithelial tumor cells (30). Although a tree-based analysis per se cannot determine whether the selected genes are in the pathways to cancer, Fig. 1 suggests different genetic mechanisms of colon cancer if the role of the three selected genes is confirmed. There exists preliminary evidence in the literature that associates the three selected genes with colon cancer (4), but further investigation is warranted.

Selditof

Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) extends MALDI-TOF's capability by incorporating an element of chromatog-raphy-based selection to isolate different sets ofproteins based on their biophysical properties (24,25). By combining protein capture on chromatographic surfaces with MS and artificial intelligence, SELDI is capability of generating protein profiles reproducibly from crude biological fluids with relative high throughput. The ease and speed of screening samples have made SELDI a popular method for biomarker discovery (26). Ion signatures generated by cluster analysis has achieved high specificity and sensitivity for ovarian, prostate, and breast cancer diagnosis (27-32). Despite these impressive results, a different view argues against the commonly held idea that biomolecules or fragments of biomolecules constituting the diagnostic pattern are derived from the tumor itself, thus casting doubt on the value of using the...

PI3K and AKT

PTEN (phosphatase and tensin homolog deleted on chromosome 10), originally identified as a tumor suppressor, is a phosphatase with dual activity on lipids and proteins. PTEN act as a negative regulator of PI3K-induced signaling by dephosphorylation of Ptdlns (3,4,5)P3 at the 3' inositol position. PTEN is frequently mutated in the advance stages of human malignancies, notably glioblastoma, non-Hodgkin's lymphoma, multiple myeloma, and endometrial and prostate cancers (67,178). Thus, loss of PTEN activity results into constitutive activation of the PI3K Akt pathway. Aberrant Akt expression and activity have been reported in a number of malignancies either through amplification ofAkt or PI3K or deregulated signaling ofPI3K Akt (179). Various studies have found Akt, particularly Akt2, gene amplifications in pancreas, ovarian, breast, and stomach malignant tumors (174,180). PI3K gene amplification has been reported in number of malignancies, including ovarian and cervix...

Ptenmmac1

Has made it possible to define the importance of each on different aspects of tumor growth. The PTEN MMAC1 tumor suppressor gene is deleted or mutated in a wide variety of cancers, including prostate cancer cell lines, xenografts, and clinical samples (9,45,46). Biochemical and functional evidence that PTEN MMAC1 acted as a negative regulator of the phosphoinositide 3-kinase (PI3-kinase) Akt pathway (47) was recently established. PTEN MMAC1 was shown to exhibit the capacity of activating endogenous Akt in cells and inhibiting phosphorylation of 4E-BP1, a downstream target of the PI3-kinase Akt pathway involved in protein translation, whereas a catalytically inactive, dominant negative PTEN MMAC1 mutant enhances 4E-BP1 phosphorylation. More interestingly, elevated levels of Akt activation were detected in human prostate cancer cell lines and xenografts lacking PTEN MMAC1 expression when compared with PTEN MMAC1-positive prostate tumors or normal prostate tissue. PTEN expression loss...

Caveolin1

Caveolin-1 (cav-1), the major protein component of caveolae, plays an important role in multiple signaling pathways, molecular transport, and cellular proliferation and differentiation in prostate cancer (49-51). It was reported that cav-1 is secreted by androgen-insensitive prostate cancer cells and detected by Western blotting in the high-density lipoprotein fraction of serum specimens from patients with prostate cancer (52,53), indicating that serum cav-1 has the power to differentiate between prostate cancer and benign prostatic hyperplasia patients and the potential to be an important biomarker for prostate cancer. It is recently established that cav-1 expression is significantly increased in primary and metastatic human prostate tumors after androgen ablation therapy (54). Also, cav-1 is secreted by androgen-insensitive prostate carcinoma cells and this secretion is regulated by steroid hormones. In cases of clinically determined, localized prostate carcinoma, it was found that...

Angiogenesis markers

A different angiogenic factor, Endothelin-1, was found in high concentration in seminal fluid that appeared to be important in prostate cancer development and progression (23). It stimulates prostate cancer cell proliferation in vitro and enhances the mitogenic effects of insulin-like growth factor-1 and other growth factors, and it shows increased expression in prostate cancer primary tumor specimens and metastases (24). Endothelin-1 seems to play a major role in the growth and angiogenesis of prostate cancer and in the pathophysi-ology of its metastasis to bone (25).

EZH2 and Syndecan1

Recent analysis by gene expression profiling shows that the polycomb group protein enhancer of zeste homolog 2 (EZH2) was overexpressed in hormone-refractory, metastatic prostate cancer. Clinically localized prostate cancers that express higher concentration of EZH2 demonstrated a poorer prognosis, suggesting that dysregulated expression of EZH2 might play a role in the progression of prostate cancer. It might be considered, given this observation, as a marker that distinguishes indolent prostate cancer from those aggressive forms (74). More recently, Zellweger et al. tested several molecular markers on a prostate tissue microarray (TMA) (67) that included syndecan-1 (CD-138), a proteoglycan that has been found to be of prognostic importance in various human tumors (108-112). They also performed the analysis of respective expression status of Ki-67, bcl-2, p53, CD-10 (neutral endopeptidase), and syndecan-1 (CD-138) by immunohistochemistry. This tissue micro-array analysis demonstrated...

Bax Inhibitor1

Grzmil et al. recently conducted some analysis work of differential gene expression of putative prostate tumor markers by comparing the expression levels of over 400 cancer-related genes using the cDNA array technique in a set of capsule-invasive prostate tumor and matched normal prostate tissue (73). Using Northern blot and Western blot analyses, they confirmed the overexpression of bax inhibitor-1 (BI-1) in prostate carcinoma and prostate cancer cell lines. Using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), they successfully detected upregulated BI-1 expression in 11 of 17 prostate tumors on intact RNAs from 17 paired laser-captured microdissected epithelial tissue samples. In addition, it was demonstrated that BI-1 expression was downregulated in stromal cells as compared to matched normal epithelial cells of the prostate. In situ hybridization experiments on prostate sections also revealed that BI-1 expression was mainly restricted to epithelial...

Future of psa

Most prostate cancers have very slow growth autopsy studies show increasing occurrence of a microscopic malignant lesion in the prostate gland without any other clinical evidence of the disease among older men 30 at > 50 yr, > 40 at > 75 yr, and approaching 100 at > 90 yr (63). Because any cancer treatment has significant morbidity associated with it, a controversy in the success of PSA in detecting early CaP has been raised. If the malignancy is of slow growth, could its early detection and aggressive treatment result in unnecessary inconvenience of the patients and economic cost For this reason, a search is on to detect the most dangerous of the CaP the fast-growing, life-threatening ones. The PSA velocity has been used unsuccessfully in this regard, and newer markers are being sought. One example is the application of polymerase chain reaction (PCR) and reverse transcriptase PCR (RT-PCR) to detect micrometastatic prostate cancer cells (64). Another approach is the use of...

Tumor markers

Tumor markers can be of great value in several aspects of cancer treatment. For prostate cancer (CaP) the use of markers has become daily routine. Prostate-specific antigen (PSA) has long since been used as a serum tumor marker to detect relapse of CaP (15). Moreover, PSA is used for population screening and diagnosis. Recently, DD3PCA3 has been described as the most CaP-specific gene that is strongly overexpressed in > 95 of primary CaP specimens and in CaP metastasis (16,17). Evaluation of a time-resolved fluorescence-based quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for the detec tion of DD3PCA3 transcripts in urinary sediments obtained after extensive prostatic massage showed a high negative predictive value for the presence of CaP (18). The use of this CaP-specific marker could have a great impact for the reduction of the number of prostate-biopsies currently needed to detect CaP.

Vegf Vegfr Complex

Prostate-Specific Membrane Antigen Prostate-specific membrane antigen (PSMA) is a 750-amino-acid type II transmembrane glycoprotein of approximately 100 kDa. It has at least two enzymatic activities (1) N-acetylated a-linked L-amino dipeptidase (NAALADase), an enzyme involved in regulation of excitatory signaling in the brain, and (2) y-glutamyl carboxypeptidase (folate hydrolase). PSMA was defined originally by mAb 7E11, which binds to an intracellular epitope of human PSMA (84,85). A number of other anti-PSMA mAbs have since been developed that bind to the extracellular domain of human PSMA, such as mAbs J591, J415, J533, and E99 (86). Expression of PSMA is restricted to prostatic tissue, including normal prostatic epithelium, benign prostatic secretory-acinar epithelium, prostatic intra-epithelial neoplasia, and prostatic adenocarcinoma cells (87,88). Interestingly, PSMA is also expressed consistently and abundantly on vascular endothelium in a wide variety of primary and...

KGF and Tumors

In patients with advanced stage squamous cell carcinoma of the head and neck, levels of KGF mRNA were significantly lower than in normal mucosa (99). KGF expression was also lower in endometrial adenocarcinoma tissue than in normal cycling endome-trium, without any corresponding reduction in KGFR expression (100). In normal human bladder, KGFR is expressed throughout most of the urothelium however, in transitional cell bladder carcinomas, receptor expression was markedly reduced (101). Moreover, the extent of this reduction correlated with prognosis, and reintroducing KGFR was later found to inhibit the growth of bladder tumors (102). In human and rat prostate cancer cells, loss of KGFR resulting from splicing events was thought to be a trigger for androgen independence and tumor progression (103,104). Similar to human bladder tumor cells, introducing KGFR in rat prostatic cancer cells inhibited tumor cell growth (105). Furthermore, KGFR was shown to be absent in salivary gland...

Combination Therapy

Most of the studies examining the analogs of rapamycin have focused on establishing the safety of these compounds and it use as a single agent usually in patients previously treated with other drugs. However, like many past regimens developed to treat cancer, it is quite likely that compounds that target mTOR will prove more effective in combination with other chemotherapeutic agents directed against other molecular targets. There is already some preliminary data indicating that this might be the case in mouse models of prostate cancer. A number of possible approaches with combination therapy could be imagined. Treatment with rapamycin followed by the timed addition of drugs targeting S-phase, such as irinotecan, might have an additive effect in tumors. For tumors where treatment with mTOR inhibitors might cause a general slowing of growth without a significant accumulation of Gl-phase cells, concomitant therapy with compounds such as interferon-a or other compounds inducing general...

Clinical Studies

Partial responses were observed in 14 of patients (3 21), and an additional 24 of patients (5 21) achieved stable disease lasting for more than 3 mo in this study. Partial re-sponders included one patient with ovarian cancer, who received 5 mg kg of pertuzumab one with prostate cancer, who received 15 mg kg of pertuzumab and one patient with a pancreatic neuroendocrine cancer who received 15 mg kg of pertuzumab (14). Two of these patients (ovarian and pancreatic cancer) remained in remission and received pertuzumab for over a year since the start of therapy. Pertuzumab was well tolerated at doses up to 15 mg kg, as a majority of adverse events were of grade 1 and 2, with the most frequently reported adverse events being vomiting, nausea, fatigue, rash, anemia, abdominal pain, and diarrhea. Skin rash and diarrhea occurred in about one-third of the patients. No significant Based on these promising results, phase II studies have been initiated in ovarian cancer, prostate cancer,...

Biochemistry of psa

First described by Wang et al. in 1979 (10), PSA is a single-chain glycoprotein neutral serine protease of240 amino acids secreted by the prostate epithelium and CaP cells (1113). A glycoprotein monomer with a molecular weight of 33,000-34,000, PSA contains 240 amino acids (10-14). Among the many PSA-like kallikreins that have been discovered so far, PSA is named human kallikrein 3 (hK3) (11). PSA is involved in the lysis of seminal coagulum and is one of the predominant proteins present in the prostatic fluid. PSA catalyzes the proteolytic degradation of gel-forming proteins secreted by human seminal vesicles and mediates the progressive activation of sperm motility. Even though PSA has been documented to be present in some nonprostate tissues e.g., periurethral (15-18) and parotid glands (19) in both men and women, and in about 30 of breast tumor specimens (20) , no significant contribution of PSA from these sources to serum PSA has so far been demonstrated. The importance of PSA as...

Variants of PSMA

Psma Binding

Prostate-specific membrane antigen is alternatively spliced to produce at least three variants (Fig. 1B), most important of which is PSM', the cDNA of which is identical to PSMA except for a 266-nucleotide region near the 5' end of PSMA cDNA (nucleotides 114380), which codes for the transmembrane region of the protein. Therefore, PSM' is located in the cytoplasm. Su and co-workers (10) used RNAse protection assays to examine the expression of PSMA and PSM' in normal vs benign prostate hyperplasia (BPH) vs prostate cancers. They found increasing expression of PSMA in tumors relative to normal controls and generated a tumor index based on the PSMA PSM' ratio, which is 9-11 in LNCaP cells, 3-6 in prostatic carcinoma, 0.75-1.6 in BPH, and 0.075-0.45 in normal prostate (Table 1). The enzymatic activity of the alternatively spliced version of PSMA PSM', has not been undisputedly proven. Evidence in support for the cytoplasmic locations of this form in LNCaP cells has been provided by two...

BRCA1 and BRCA2

Hereditary breast cancer accounts for 5-10 of breast cancers. The majority of familial breast cancers are associated with mutations in BRCA1 or BRCA2, and BRCA1 is mutated in 80 of familial breast and ovarian cancer. These genes are rarely mutated in sporadic breast or ovarian cancers (46). Carriers of mutations in these genes are also at increased risk for prostate and pancreatic cancers, although the risk is lower than for breast cancer (47). BRCA1 and BRCA2 act as a tumor suppressors and negative regulators of mammary epithelial differentiation. The mechanisms through which these genes affect this role are not clear, but the proteins appear to function in the same genetic pathways, yet with distinct functions (48,49). Consistent with these observations, the presentation of cancers in patients harboring mutations in BRCA1 or BRCA2 are similar but not identical (reviewed in ref. 50).

And Neil H Bander MD

Suitability of Prostate Cancer as Target for mAb-Based Therapy Prostate-Specific Membrane Antigen Development of PSMA-Specific mAbs Clinical Studies References Despite advances in the diagnosis and therapy of prostate carcinoma, it remains a serious medical problem accounting for a large number of malignancies in men each year. Although earlier detection is now possible, many patients develop advanced metastatic disease even when there is no evidence of spread at the time of initial diagnosis and treatment. These metastatic sites could initially be controlled by hormonal therapy but ultimately become resistant and the disease enters an aggressive stage for which there is currently no satisfactory therapy. In response to this perceived need, monoclonal antibodies have been considered a direct biological modifier of the disease and a vehicle to deliver radioactive metals and other cytotoxic agents to disseminated tumor sites. J591 is a monoclonal antibody that recognizes the internal...

The Sentinel Node Concept Related to Main Tumor Types and Subtypes Applicability in Daily Routine Work

Prostate Cancer an 449 Serum Values of Prostate-specific Antigen and Prostate Acid of Prostate 455 to Results in Prostatectomy Specimens 456 of Prostate 463 Does Radical Prostatectomy Improve the Results in Lymph Node- of Sentinel Nodes in Prostate Cancer 470 Performance of the Labeling Procedure in Prostate Cancer Cases 474 Is FDG-PET Helpful in Detection and N-staging of Prostate Cancer . . 477 Can Sentinel Node Labeling be Improved According to Animal Therapy Regimens for Prostate

Definition of the Sentinel Lymph Node and Basic Principles of Detection

The sentinel lymph node (SLN) is defined as the first regional lymph node to receive lymphatic fluid from a malignant tumor. Therefore, this node is a sentinel for second metastatic lymph node stations and for labeling regional tumor spread. (For editorials and overviews see Veronesi et al. 1997 Dixon 1998 della Rovere and Bird 1998.) This node is useful for locoregional tumor staging and for subsequent individual related further surgical strategies. In some ways, this has been a logical development after the more or less successful use of lymph-angiography by many radiologists in the 1970s. This older method has been used to detect cancer metastases or infiltration of lymph nodes, for example in cases of prostate or bladder cancer as well as in Hodgkin or non-Hodgkin lymphomas. This staging procedure has been developed for the following tumor categories breast cancer (already used in many clinics, but in others still in development) malignant melanomas (already well developed) lung...

Pancreatic Organogenesis In Mammalian Models

Mistl is a recently identified Class II bHLH transcription factor that is only expressed in acinar cells of the pancreas, although it is expressed in a variety of secretory extrapancreatic tissues, such as salivary acini, and serous cells of the stomach, prostate, and seminal vesicles.66,67 In the embryonic pancreas, Mistl is detectable early (E10.5) in the dorsal pancreatic bud at E14, when acinar structures are histologically distinct, Mistl expression is confined to acinar cells. Knockout mice null for Mistl survive and at birth are reported to be grossly undistinguishable from control littermates. Examination of Mistl - mice later in life reveals defects in acinar cell organization and loss of acinar cell polarity similar defects are also found in salivary and seminal vesicle epithelia. 68 The bHLH domain of Mistl is highly similar to that found in the recently characterized Drosophila transcription factor dimmed, which is required for amplified levels of secretory activity in...

Materials and Methods

Only direct information available in almost all of the embryos and some of the fetuses and allow comparison between the present data and those of all major previous studies. It should be stressed that when added to the text these lengths indicate the earliest observation of a certain developmental event or a developmental period, and also that variation in development between embryos of the same age and length was considerable. The study comprises all that is currently designated as perineum, from skin to the pelvic diaphragm in the whole diamond-shaped region bordered by the pubic symphysis, ischial tuberosities, and os coccygis (Williams 1989 Moore and Dalley II 1996), and to which are added from an embryological perspective the urethra and muscular coat in the female, and the prostatic urethra and related muscular coat, prostate and colliculus seminalis with ejaculatory ducts and prostatic utricle in the male. Since the designation perineum is often used for the area between the...

Diagnosis of Primary Tumors

Tiated thyroid carcinomas, neuroendocrine tumors, hepatocellular carcinomas, mature teratomas, and prostate cancer. In general, FDG-PET should not be used as a screening test for identifying cancer. Rather, patients should be referred to PET imaging for further evaluation and characterization of suggestive masses found by conventional imaging modalities. Although PET offers excellent diagnostic accuracy for many tumors, it cannot substitute for histological verification. The clinical application of FDG-PET in the diagnosis of primary tumors is therefore often restricted to high-risk patients about to undergo surgery or to guidance of invasive procedures by identifying viable tumor tissue.

Telomerase function genetic instability cell proliferation and cancer metastasis

Control may involve the cell cycle control genes, p53 and rb. It has been postulated that diminution of the telomere beyond a critical length might activate p53 leading to Ml senescence. But telomerase-dependent immortalisation of cells, together with the inactivation of p53 or rb genes by allelic loss or mutation, is postulated to lead to M2 immortalisation. Furthermore, M2 immortalisation is postulated to lead to progression of tumours to the metastatic state (Healy, 1995). This fits in with the picture of a late contribution by p53 to the progression of colorectal cancers (see page 172 and Figure 18). The M2 immortalisation concept is also compatible with the finding that telomerase activity is detected in colorectal carcinomas but not in adenomatous polyps (Chadeneau et al, 1995). Eddington et al. (1995) believe that the activation of telomerase may be a late event in cancer progression and this may be associated also with loss of p53 gene function by genetic alteration or allelic...

Histo and Cytopathological Diagnosis

In prostate cancer treatment sentinel node labeling with 99mTc-colloids is not limited by needle biopsies taken before N-staging is carried out. Prostate cancer Gleason grade acid prostate phosphatase, pro state- specific antigen in the case of marker loss also CK (pan), P504S

P53 cancer progression and prognosis

Over-expression of p53 protein was reported in > 50 of breast cancers (Horak et al., 1991). Mutations of the gene are also common (25-40 incidence) in sporadic breast cancer, with the frequency of G-T transversions generally higher than expected, and these occur predominantly in the conserved exons 5-8. In many cases mutation of one allele is also accompanied by deletion of the second allele. In summary, p53 mutation characterises a highly aggressive form of the disease, associated with poor prognosis in both node-positive and node-negative patients (Lemoine, 1994). But, in contrast to colon cancer, these tend to be early events. It may be that the distinction lies in the fact that in tumorigenesis in the colon results from mutations in a series of genes, including the DCC gene, which produce a progressive alteration in the phenotype and p53 may have a complementary role (see page 172). Abnormalities of rb, another suppressor gene that actively regulates cell cycle progression, are...

Transduction Efficacy

The greatest strength of AdVs as a gene therapy vector lies in their very high transduction efficiency and effective expression of the transgenes. In basic science the use of AdVs guarantees reliable gene expression so that even less prominent biological effects of the studied transgenes can be recognised. In human malignant gliomas AdVs have been found more efficient than retroviruses as gene transfer vectors 5 . AdVs transduce both dividing and non-dividing cells and enter the cells mainly through coxackie- and adenovirus-receptor (CAR). CAR is known to be expressed in pancreas, brain, heart, small intestine, testes, prostate, liver and lungs but is almost non-existing in skeletal muscles and blood vessel endothelium 6 . avp3 and avp5 integrins, heparin sulphate proteoglycans and the a2 domain of the MHC class I bind AdVs in skeletal muscle 7-9 . In animals and humans first generation AdVs have been found efficient gene transfer vectors in peripheral arteries 10-13 . Furthermore,...

Subcellular localisation of p53 protein

On the basis of these observations, it may be suggested that the subcellular localisation of p53 protein might yield valuable information about the pathways of p53 functioning, especially in relation to its cooperation with other cellular proteins which might be involved with or impinge upon the processes of cellular transformation. It is conceivable, therefore, that the patterns of p53 protein staining may be related to tumour development and progression. There are several indicators in this direction. Nuclear p53 staining is far more predominant in aneuploid tumours than in diploid tumours (Sun et al., 1993). In breast cancer where both nuclear and cytoplasmic staining is seen, p53 accumulation correlates strongly with DNA ploidy, among other variables (Stenmark-Askmalm et al, 1994). There are also indications that p53 staining pattern might be related to cancer prognosis. p53 staining of both the nucleus and the cytoplasm of colorectal tumours was associated with poor survival of...

Retinoblastoma susceptibility gene rb abnormalities in cancer

Loss of heterozygosity at the rb locus occurs frequently in oesophageal cancers (Boynton et al., 1991). Structural changes of the gene are associated with human soft tissue tumours (Friend et al., 1987 Stratton et al., 1989). Other tumour types with rb involvement are cancer of the prostate (Bookstein et al, 1990a), leukaemias (Cheng et al., 1990 Furukawa et al., 1991), and osteocarcinomas (Toguchida et al., 1988 Shew et al., 1989).

Is the wafl dpi gene altered in cancer

Reported in colorectal cancer and somatic mutations have not been found in codons 9 through 139 that were screened (Li YJ et al., 1995). Multiple polymorphisms were seen in human brain tumours, most frequently of codon 31 - again there were no somatic mutations (Koopmann et al, 1995). Codon 31 polymorphism occurs also in normal individuals (Li YJ et al, 1995 Marchetti et al, 1995c) and, in the brain tumour study, the polymorphisms did not relate to histological type (Koopmann et al, 1995). Jung et al (1995b) also investigated gliomas for wafl cipl abnormalities. Surprisingly, wafl cipl protein levels were low in normal brain tissue and in reactive gliosis, but were highly elevated in gliomas irrespective of grade. Glioblastoma multiforme showed elevated protein levels, in tumour samples carrying either wild-type or mutated p53- No elevation of protein occurred in anaplastic astrocytomas carrying mutant p53-Jung et al (1995b) also stated that wafl cipl gene is not deleted in gliomas....

Seminal plasma factors that affect sperm motility

Semenogelin (I and II) is the main protein of the semen coagulum in humans and represents upto 20 of seminal plasma proteins (Robert and Gagnon, 1999). After ejaculation, it is rapidly degraded by prostate specific antigen, a chymotrypsin-like protease (Robert and Gagnon, 1999). In vitro, sperm motility is inhibited by semenogelin and one of the degradation polypeptides, called the seminal plasma motility inhibitor, when added at levels similar to those found in semen (Robert and Gagnon, 1999). Semenogelin and its degradation peptides are associated with Triton-soluble and -insoluble sperm fractions and may have various biological effects, such as an inhibin-like activity, increase in sperm hyaluronidase activity, zinc shuttling and dynein ATPase inhibition (Robert and Gagnon, 1999).

Mucins In Diagnosis And Therapy

Ovary, prostate, lung, and esophagus and is absent in most normal tissues. TAG-72 has been identified by its immunoreactivity with the monoclonal antibody (MAb) B72.3, a murine MAb, which was developed by the immunization of mice with a membrane-enriched fraction of human met-astatic breast carcinoma tissue. The epitope recognized by MAb B72.3 is sialyl-Tn, a unique disaccharide present in multiple copies on the tumor-associated mucin TAG-72.

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