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Pharmacogenetics of Cancer Chemotherapy
Present clinical algorithms assign adjuvant chemotherapy according to prognosis,
but clinical decision-making would be greatly improved if reliable predictive mark-
ers were available to identify which subsets of patients benefi t most from treatment.
Another problem is that unpredictable effi cacy and high levels of systemic toxicity
are common in cancer chemotherapy. Genetic variability in drug-metabolizing
enzymes and signaling pathways affects chemotherapy-related toxicity and treat-
ment outcome in cancer. Pharmacogenetics, therefore, is particularly appealing for
oncology. Cytotoxicity to chemotherapy agents, 5-fl uorouracil and docetaxel, which
have distinct mechanisms of action, are heritable traits varying with dose.
Polymorphisms in thymidylate synthase (TS), MTHFR, and FCGR3A, as well as
the polymorphic DNA repair genes XPD and XRCC1, infl uence response to chemo-
therapy and survival outcomes.
In breast and colorectal cancer, polymorphisms in metabolic enzymes involved
in tamoxifen and irinotecan therapies has led the FDA to address genetic factors
relevant to patient consideration of treatment with these compounds. Tamoxifen
therapeutic failure in breast cancer has been associated with reduced CYP2D6
activity due to ineffi cient activation of tamoxifen. Irinotecan toxicity in colorectal
cancer is more common in patients with reduced-activity UGT1A alleles, resulting
in excessive exposure to the potent SN-38 metabolite. In colorectal and lung can-
cers, somatic mutations in the EGFR and downstream signaling molecules have
been associated with the therapeutic outcome of EGFR-directed therapies. Current
advances in single gene − UGT1A1, CYP2D6, EGFR, and KRAS − or multigene
analysis, contribute to optimizing breast, colorectal, and lung cancer therapy high-
lighting how pharmacogenetics has helped in personalized decision-making for
patient management (Snozek et al. 2009 ).
CYP 1A2
The enzyme product of CYP1A2 is involved in a number of environmental carcino-
gens as well as anticancer drugs such as tamoxifen and drugs used for preventing
nausea associated with chemotherapy such asondasetron. Other therapeutic drugs
metabolized by CYP1A2 include acetaminophen, amitriptyline, clomipramine, clo-
zapine, diazepam, methadone, propranolol, and tacrine. This shows the complexity
of situations that can be encountered with co-administration of drugs in cancer
patients in the presence of carcinogens. There are marked interindividual differ-
ences in capacity for CYP1A2 induction, which correlate with genetic polymor-
phisms termed CYP1A2F. Identifi cation of individuals who have different capacities
for induction of CYP1A2 may be an indicator of increased risk of drug interactions
or drug toxicity when treated with drugs metabolized by CYP1A2. Genotyping of
cancer patients prior to treatment may help to individualize treatment to avoid
adverse reactions and increase the effectiveness of therapy.
10 Personalized Therapy of Cancer