Polymorphisms Relevant To Cancer Chemotherapy

The basis of many forms of cancer chemotherapy involves the administration of maximum tolerated dosages with the goal of inflicting the greatest damage to malignant cells while causing the least damage to normal tissue. Genetic variations of drug-inactivating enzymes in normal tissues may increase the risk of severe toxicity or even death. As mentioned above, TMPT-deficient (homozy-gous; -0.3% of the population) individuals treated for acute lymphoblastic leukemia with standard doses of mercaptopurine, thioguanine and azathioprine (immunosuppressant) may experience severe and potentially lethal bone marrow toxicity. A dose-reduction of up to 15-fold may be needed to avoid hematotoxicity in these patients (Evans et al., 1991). TPMT genotyping or phenotyping (by assessing red blood cell enzyme levels) prior to the institution of therapy with any of these agents has become accepted practice at some medical centers (Sadee, 2000).

Several similar examples have been documented (Iyer and Ratain, 1998): patients with variant DPyDH cannot inactivate 5-fluorouracil, resulting in myelosuppression and neurotoxicity, while overexpression of DPyDH in tumors is linked to resistance to that drug; N-acetyltransferase 2 rapid acetylators (30%-60% of Caucasians and 80%-90% of Asians) are at risk of greater bone marrow toxicity with amonafide treatment (topo-isomerase II inhibitor); and patients who have a genetic deficiency of glucuronidation because of a variant promoter of UGT-glucuronosyltransferase UGT1A1 are at increased risk of myelosuppres-sion and diarrhea when treated with the topoisomerase I inhibitor irinotecan. At least one example of an activating variant of a co-factor/ enzyme has been reported: mutations of NAD(P)H(nicotinamide-adenine dinucleotide phosphate, reduced form):quinone oxidoreductase (which activates cytotoxic anti-tumor quinones such as mitomycin C) protect against cytoxic metabolites, but also may reduce anti-tumor efficacy (Gaedigk et al., 1998).

Growth factor receptors may be overexpressed in some tumors, potentially affecting the efficacy of chemotherapy. One example of this involves the humanized monoclonal antibody trastuzumab (Herceptin™), which was designed to target an oncogene (HER2/neu) that is overexpressed in some breast cancers and other cancers with poor prognoses. Trastuzumab, when given with paclitaxel and doxorubicin, enhances the cytotoxic effects of the anti-neoplastic agents in breast cancer tissues with high HER2/neu expression (Baselge et al., 1998). Some researchers suggest that an optimal approach to cancer chemotherapy would involve genotyping both malignant and normal cells when feasible (Sadee, 2000).

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