Colorectal cancer mechanisms

As with c-erbB, overexpression of the suppressor p53 gene product has been found in different cancers (H3). Initially, it was believed that the detection of p53 protein in tumors meant the presence of a mutant gene product. However, we now know that normal p53 protein can be overexpressed in response to certain stimuli and stabilized by interaction with both cellular and viral proteins (H3). Irrespective of the mechanism giving rise to elevated protein levels, overexpression of p53 has been shown to be a prognostic marker in both breast and colorectal cancers (D8). In some studies, the presence of high levels of p53 has been shown to be a prognostic marker in axillary node-negative breast cancer patients (H3). 

Williams CS, Smalley W, DuBois RN. Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest 1997 100 1325-1329. 

Levamisole (Ergamisol) is an antiparasitic drug that has been found to enhance T-ceU function and cellular immunity. The drug improves survival of patients with resected colorectal cancers when combined with 5-fluo-rouracil the mechanism of this interaction is not known. Levamisole does not have antitumor activity against established or metastatic cancer and has not been found useful in the adjuvant therapy of cancers other than colorectal cancer. 

Wang TL, Diaz LA, Jr., Romans K et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl AcadSci USA 2004 101 3089-3094. 

Oxaliplatin is a third generation diaminocyclohexane platinum analog. Its mechanism of action is identical to that of cisplatin and carboplatin. However, it is not cross-resistant to cancer cells that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects. This agent was recently approved for use as second-line therapy in metastatic colorectal cancer following treatment with the combination of fluorouracil-leucovorin and irinotecan, and it is now widely used as first-line therapy of this disease as well. Neurotoxicity is dose-limiting and characterized by a peripheral sensory neuropathy, often triggered or worsened upon exposure to cold. While this neurotoxicity is cumulative, it tends to be reversible—in contrast to cisplatin-induced neurotoxicity. 

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it increases the magnitude of delayed hypersensitivity or T cell-mediated immunity in humans. In immunodeficiency associated with Hodgkin s disease, levamisole has been noted to increase the number of T cells in vitro and to enhance skin test reactivity. Levamisole has also been widely tested in rheumatoid arthritis and found to have some efficacy. However, it has induced severe agranulocytosis (mainly in HLA-B27-positive patients), which required discontinuation of its use. The drug may also potentiate the action of fluorouracil (5-FU) in adjuvant therapy of colorectal cancer, and this combination has been approved for clinical use in the treatment of Dukes class C colorectal cancer after surgery. Its use in these cases reduces recurrences, and the mechanism... 

The mechanism by which the KCNK9 gene overexpresses in human colorectal cancers is a good example of chromosomal gain or genomic amplification. Mu et al. (2003) have identified KCNK9 as a new protooncogene... 

Cahill et alJ (discussed by Weaver and Weinberg ) have shovra that the mechanisms controlling the proper separation of chromosomes during cell division are defective in colorectal cancer cells, causing aneuploidy. 

The biochemical mechanisms that may have led to the C G T A mutation are discussed later. The mechanisms are consistent with epidemiological data suggesting that a low consumption of fruits and vegetables leads to an elevated risk for colorectal cancer. One might ask, "How can mutations involving CG T A, rather than other base changes, be associated with a diet low in fruits and vegetables " Possible answers are revealed in what follows. 

---