Pharmacogenetics and Cancer

  • Warren D. Kruger
  • Kenneth D. Tew


It has been known for more than 30 years that individuals vary in their ability to metabolize therapeutically useful molecules. This variation is due in large part to genetic differences among individuals. Humans are exposed to thousands of natural and synthetic compounds, in addition to drugs, that must be metabolized to become carcinogenic. Genetic variation in the encoded enzymes involved in this metabolism is thought to be the basis for some of the differences in cancer susceptibility among individuals. The study of how genetic variation affects the metabolism of drugs and other compounds is called pharmacogenetics.


Cancer Susceptibility CYP2D6 Gene MSPI Polymorphism Germ Line Polymorphism DPYD Gene 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Smith G, Stanley LA, Sim E, et al.: Metabolic polymorphisms and cancer susceptibility. Cancer Sury 1995, 25: 27–65.Google Scholar
  2. 2.
    Nelson DR, Koymans L, Kamataki T, et al: P450 super-family: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996, 6: 1–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Gonzalez FJ: The role of carcinogen-metabolizing enzyme polymorphisms in cancer susceptibility. Reprod Toxicol 1997, 11: 397–412.PubMedCrossRefGoogle Scholar
  4. 4.
    Goto I, Yoneda S, Yamamoto M, Kawajiri K: Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. Cancer Res 1996, 56: 3725–3730.PubMedGoogle Scholar
  5. 5.
    Crofts F, Taioli E, Trachman J, et al. Functional significance of different human CYP1A1 genotypes. Carcinogenesis 1994, 15: 2961–2963.PubMedCrossRefGoogle Scholar
  6. 6.
    Horio Y, Takahashi T, Kuroishi T, et al. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res 1993, 53: 1–4.PubMedGoogle Scholar
  7. 7.
    Mitsudomi T, Oyama T, Kusano T, et al.: Mutations of the p53 gene as a predictor of poor prognosis in patients with non-small-cell lung cancer. J Natl Cancer Inst 1993, 85: 2018–2023.PubMedCrossRefGoogle Scholar
  8. 8.
    Kawajiri K, Eguchi H, Nakachi K, et al.: Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer. Cancer Res 1996, 56: 72–76.PubMedGoogle Scholar
  9. 9.
    Storey A, Thomas M, Kalita A, et al.: Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 1998, 393: 229–234.PubMedCrossRefGoogle Scholar
  10. 10.
    Rebbeck TR: Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prey 1997, 6: 733–743.Google Scholar
  11. 11.
    McWilliams JE, Sanderson BJ, Harris EL, et al.: Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiol Biomarkers Prey 1995, 4: 589–594.Google Scholar
  12. 12.
    Deakin M, Elder J, Hendrickse C, et al.: Glutathione Stransferase GSTT1 genotypes and susceptibility to cancer: studies of interactions with GSTM1 in lung, oral, gastric and colorectal cancers. Carcinogenesis 1996, 17: 881–884.PubMedCrossRefGoogle Scholar
  13. 13.
    Elexpuru-Camiruaga J, Buxton N, Kandula V, et al.: Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P-450 (CYP2D6) loci. Cancer Res 1995, 55: 4237–4239.PubMedGoogle Scholar
  14. 14.
    Dekant W, Vamvaka S, Anders MW: Formation and fate of nephrotoxic and cytotoxic glutathione S-conjugates: cysteine conjugate beta-lyase pathway. Adv Pharmacol 1994, 27: 114–162.Google Scholar
  15. 15.
    Meyer UA, Zanger UM: Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 1997, 37:269–296.Google Scholar
  16. 16.
    Mahgoub A, Idle JR, Dring LG, et al.: Polymorphic hydroxylation of Debrisoquine in man. Lancet 1977, 2: 584–586.PubMedCrossRefGoogle Scholar
  17. 17.
    Gonzalez FJ, Skoda RC, Kimura S, et al.: Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 1988, 331: 442–446.PubMedCrossRefGoogle Scholar
  18. 18.
    Caporaso N, DeBaun MR, Rothman N: Lung cancer and CYP2D6 (the debrisoquine polymorphism): sources of heterogeneity in the proposed association. Pharmacogenetics 1995, 5: S129–134.PubMedCrossRefGoogle Scholar
  19. 19.
    Lang NP, Butler MA, Massengill J, et al.: Rapid metabol- ic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne hetero- cyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol Biomarkers Prey 1994, 3: 675–682.Google Scholar
  20. 20.
    Morrison GB, Bastian A, Dela Rosa T, et al.: Dihydropyrimidine dehydrogenase deficiency: a pharmacogenetic defect causing severe adverse reactions to 5-fluorouracil-based chemotherapy. Oncol Nurs Forum 1997, 24: 83–88.PubMedGoogle Scholar
  21. 21.
    Lu Z, Zhang R, Diasio RB: Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res 1993, 53: 5433–5438.PubMedGoogle Scholar
  22. 22.
    McMurrough J, McLeod HL: Analysis of the dihydropyrimidine dehydrogenase polymorphism in a British population. Br J Clin Pharmaco1, 1996, 41: 425–427.Google Scholar
  23. 23.
    Ridge SA, Brown O, McMurrough J, et al.: Mutations at codon 974 of the DPYD gene are a rare event. Br J Cancer 1997, 75: 178–179.PubMedCrossRefGoogle Scholar
  24. 24.
    Van Kuilenburg AB, Vreken P, Beex LV, et al.: Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity. Eur J Cancer 1997, 33: 2258–2264.PubMedCrossRefGoogle Scholar
  25. 25.
    Wei X, McLeod HL, McMurrough, J, et al.: Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest 1996, 98, 610–615.PubMedCrossRefGoogle Scholar
  26. 26.
    Morgan AS, Sanderson PE, Borch RF, et al.: Tumor efficacy and bone marrow sparing properties of Ter 286, a cytotoxin activated by glutathione S-transferase. Cancer Res 1998, 58: 2568–2575.PubMedGoogle Scholar
  27. 27.
    Nebert DW, McKinnon RA, Puga A: Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol 1996, 15: 273–280.PubMedCrossRefGoogle Scholar
  28. 28.
    Kadlubar FF, Butler MA, Kaderlik KR, et al.: Polymorphisms for aromatic amine metabolism in humans: relevance for human carcinogenesis. Environ Health Perspect 1992, 98: 69–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Tew KD: Glutathione associated enzyme in anticancer drug resistance. Perspectives in cancer research. Cancer Res 1994, 54: 4313–4320.PubMedGoogle Scholar

Copyright information

© Current Medicine, Inc. 2000

Authors and Affiliations

  • Warren D. Kruger
  • Kenneth D. Tew

There are no affiliations available

Personalised recommendations