Genetic Basis ofChemotherapy Resistance in Colorectal Cancer

In addition to the overexpression of genes involved in drug metabolism and transport, resistance to therapy might also result from the lack of expression of genes involved in cell cycle and stress response mechanisms. One such example involves the tumor suppressor gene TP53—one of the most frequently mutated genes in human cancers. The wild-type protein encoded by TP53 has been found to be mutated or underexpressed in more than half of human tumors analyzed so far. Following genotoxic injury p53 typically functions to induce cell cycle arrest to repair DNA damage or, under certain conditions, induce apoptosis (through the G1-G2 DNA-damage checkpoint). When mutated, the lack of functional p53 might contribute to drug resistance by making the cell unable to undergo apoptosis in response to DNA damage. Some authors have even speculated that p53 might actually play a dual role after exposure to cytotoxic drug treatment, activating either mechanisms that lead to apoptosis or launching processes that direct DNA repair and survival of the cell (29).

There are a few examples of successful targeting of defective tumor suppressor gene function in colorectal cancer. One is the transfer of the wild-type p53 into cancer cells, with mutated p53 leading to enhanced chemosensitivity and increased apoptosis (30-33); Other studies have examined whether the activity of certain p53 mutants can be restored by second-site suppressor mutations that introduce an additional DNA contact and thereby correct the local structural distortion or increase the stability of the core domain structure (34). Small molecules have been developed to stabilize the wild-type and mutant p53 core domain, presumably by binding specifically to the native protein. Correction of mutant folding restores p53 function to cancer cells and inhibits tumor growth in mice (34). In one such example, a drug prototype CP-31398 achieves a 75% suppression of growth in colorectal carcinoma xenograft models (35,36). The compound is thought to increase the thermostability of p53 through its expected binding in a bivalent manner to hydrophobic and acidic sites. However, despite these promising early results cellular concentrations are not maintained high enough for practical treatment and further investigation is warranted.

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