Pharmacogenetics and cancer therapy (original) (raw)

• Ratain, M. J. & Relling, M. V. Gazing into a crystal ball — cancer therapy in the post-genomic era. Nature Med. 7, 283–285 (2001).
  CAS PubMed Google Scholar
• Klausner, R. D. Cancer, genomics, and the National Cancer Institute. J. Clin. Invest. 104, 15–17 (1999).
  Google Scholar
• Vogel, F. Moderne probleme der humangenetik. Ergebnisse Inneren Medizin und Keinderheilkunde 12, 52–125 (1959).
  Google Scholar
• Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).
  CAS PubMed Google Scholar
• Spannbrucker, N., Eichelbaum, M., Steinke, B. and Dengler, H. J. A human genetic defect in the metabolism of sparteine. Verh. Dtsch. Ges. Inn. Med. 84, 1125–1127 (1978).
  Google Scholar
• Gonzalez, F. J. et al. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331, 442–446 (1988).The genetic basis underlying individual variations in responses to the antihypertensive drug debrisoquine. Poor drug metabolizers were found to express negligible amounts of the cytochrome P450 enzyme P450db1. The authors cloned the human P450db1 cDNA and purified the protein, discovering one of the most commonly occuring mutations. This was the start of modern pharmacogenetics.
  CAS PubMed Google Scholar
• Mortimer, O. et al. Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1. Clin. Pharmacol. Ther. 47, 27–35 (1990).
  CAS PubMed Google Scholar
• Meyer, U. A. The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. Pharmacol. Ther. 46, 297–308 (1990).
  CAS Google Scholar
• Meyer, U. A. & Zanger, U. M. Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu. Rev. Pharmacol. Toxicol. 37, 269–296 (1997).
  CAS PubMed Google Scholar
• Johansson, I. et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc. Natl Acad. Sci. USA 90, 11825–11829 (1993).
  CAS PubMed PubMed Central Google Scholar
• Sachidanandam, R. et al. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933 (2001).The work of several large collaborative groups, whose goal was to characterize the frequency and distribution characteristics of single nucleotide polymorphisms across the entire human genome.
  CAS PubMed Google Scholar
• Pastinen, T. et al. A system for specific, high-throughput genotyping by allele-specific primer extension on microarrays. Genome Res. 10, 1031–1042 (2000).
  CAS PubMed PubMed Central Google Scholar
• Hoogendoorn, B. et al. Cheap, accurate and rapid allele frequency estimation of single nucleotide polymorphisms by primer extension and DHPLC in DNA pools. Hum. Genet. 107, 488–493 (2000).
  CAS PubMed Google Scholar
• Giordano, M., Mellai, M., Hoogendoorn, B. & Momigliano-Richiardi, P. Determination of SNP allele frequencies in pooled DNAs by primer extension genotyping and denaturing high-performance liquid chromatography. J. Biochem. Biophys. Methods 47, 101–110 (2001).
  CAS PubMed Google Scholar
• Mein, C. A. et al. Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation. Genome Res. 10, 330–343 (2000).
  CAS PubMed PubMed Central Google Scholar
• Hessner, M. J., Budish, M. A. & Friedman, K. D. Genotyping of factor V G1691A (Leiden) without the use of PCR by invasive cleavage of oligonucleotide probes. Clin. Chem. 46, 1051–1056 (2000).
  CAS PubMed Google Scholar
• Pfost, D. R., Boyce-Jacino, T. & Grant, D. M. A SNP shot: pharmacogenetics and the future of drug therapy. Trends Biotechnol. 18, 334–338 (2000).
  CAS PubMed Google Scholar
• Pui, C. H. & Evans, W. E. Acute lymphoblastic leukemia. N. Engl. J. Med. 339, 605–615 (1998).
  CAS PubMed Google Scholar
• Elion, G. B. The purine path to chemotherapy. Science 24, 441–447 (1989).
  Google Scholar
• Relling, M. V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine _S_-methyl-transferase gene locus. J. Natl Cancer Inst. 91, 2001–2008 (1999).
  CAS PubMed Google Scholar
• Lennard, L., Lilleyman, J. S., Van Loon, J. & Weinshilboum, R. M. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225–229 (1990).
  CAS PubMed Google Scholar
• Lennard, L., Gibson, B. E., Nicole, T. & Lilleyman, J. S. Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch. Dis. Child 69, 577–579 (1993).
  CAS PubMed PubMed Central Google Scholar
• Dervieux, T. et al. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res. 61, 5810–5816 (2001).
  CAS PubMed Google Scholar
• Weinshilboum, R. M. & Sladek, S. L. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32, 651–662 (1980).This survey of 298 blood donors established a trimodal distribution for erythrocyte thiopurine methyltransferase activity, and classical family studies established that the three phenotypes were due to monogenic autosomal codominant inheritance. The authors suggested that the polymorphism could be used to predict response to thiopurine therapy, which was subsequently verified in many studies.
  CAS PubMed PubMed Central Google Scholar
• Tai, H. L. et al. Thiopurine _S_-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 58, 694–702 (1996).
  CAS PubMed PubMed Central Google Scholar
• Otterness, D. et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin. Pharmacol. Ther. 62, 60–73 (1997).
  CAS PubMed Google Scholar
• Yates, C. R. et al. Molecular diagnosis of thiopurine _S_-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997).A molecular genotyping method showed over 95% concordance between thiopurine S –methyltransferase (TPMT) genotype and phenotype. The study was later extended to other populations with comparable success. TPMT genotyping eventually became the first certified molecular diagnostic for identifying patients requiring dosage adjustments of chemotherapy to avoid severe toxicity.
  CAS PubMed Google Scholar
• Tai, H. L., Krynetski, E. Y., Schuetz, E. G., Yanishevski, Y. & Evans, W. E. Enhanced proteolysis of thiopurine _S_-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity. Proc. Natl Acad. Sci. USA 94, 6444–6449 (1997).
  CAS PubMed PubMed Central Google Scholar
• Weinshilboum, R. M. Human pharmacogenetics: introduction. Fed. Proc. 43, 2295–2297 (1984).
  CAS PubMed Google Scholar
• Evans, W. E. et al. Preponderance of thiopurine _S_-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J. Clin. Oncol. 19, 2293–2301 (2001).
  CAS PubMed Google Scholar
• Dervieux, T. et al. Possible implication of thiopurine _S_–methyltransferase in the occurrence of infectious episodes during maintenance therapy of acute leukemia with mercaptopurine. Leukemia (in the press).
• Relling, M. V., Hancock, M. L., Boyett, J. M., Pui, C.-H. & Evans, W. E. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93, 2817–2823 (1999).
  CAS PubMed Google Scholar
• Relling, M. V. et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354, 34–39 (1999).Overall, the incidence of irradiation-induced brain tumours is usually low, occurring in only 1–2% of patients. However, almost half of the patients who received irradiation as well as mercaptopurine, and also possessed a germ-line defect in thiopurine methyltransferase, developed brain tumours. This shows how genetic characteristics and treatment interact to create risk groups.
  CAS PubMed Google Scholar
• Relling, M. V. et al. Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 12, 346–352 (1998).
  CAS PubMed Google Scholar
• Krynetskaia, N. F., Cai, X., Nitiss, J. L., Krynetski, E. Y. & Relling, M. V. Thioguanine substitution alters DNA cleavage mediated by topoisomerase II. FASEB J. 14, 2339–2344 (2000).
  CAS PubMed Google Scholar
• Uribe-Luna, S. et al. Mutagenic consequences of the incorporation of 6-thioguanine into DNA. Biochem. Pharmacol. 54, 419–424 (1997).
  CAS PubMed Google Scholar
• Pinedo, H. M. & Peters, G. F. Fluorouracil: biochemistry and pharmacology. J. Clin. Oncol. 6, 1653–1664 (1988).
  CAS PubMed Google Scholar
• Heggie, G. D., Sommadossi, J. P., Cross, D. S., Huster, W. J. & Diasio, R. B. Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res. 47, 2203–2206 (1987).
  CAS PubMed Google Scholar
• Etienne, M. C. et al. Population study of dihydropyrimidine dehydrogenase in cancer patients. J. Clin. Oncol. 12, 2248–2253 (1994).
  CAS PubMed Google Scholar
• Lu, Z., Zhang, R. & Diasio, R. B. 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. 53, 5433–5438 (1993).
  CAS PubMed Google Scholar
• Diasio, R. B., Beavers, T. L. & Carpenter, J. T. Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5- fluorouracil-induced toxicity. J. Clin. Invest. 81, 47–51 (1988).The clinical observation of severe 5-fluorouracil toxicity in a patient served as the basis for determining its biochemical mechanism, a polymorphism that reduced dihydropyrimidine dehydrogenase activity. Family studies revealed the inherited basis for the defect.
  CAS PubMed PubMed Central Google Scholar
• Johnson, M. R. et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin. Cancer Res. 5, 2006–2011 (1999).
  CAS PubMed Google Scholar
• Van Kuilenburg, A. B. et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G→A mutation causing DPD deficiency. Clin. Cancer Res. 7, 1149–1153 (2001).
  CAS PubMed Google Scholar
• Gonzalez, F. J. & Fernandez-Salguero, P. Diagnostic analysis, clinical importance and molecular basis of dihydropyrimidine dehydrogenase deficiency. Trends Pharmacol. Sci. 16, 325–327 (1995).
  CAS PubMed Google Scholar
• Berger, R. et al. Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. Clin. Chim. Acta 141, 227–234 (1984).
  CAS PubMed Google Scholar
• Wei, X., McLeod, H. L., McMurrough, J., Gonzalez, F. J. & Fernandez-Salguero, P. Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J. Clin. Invest. 98, 610–615 (1996).This was the first study to link a defect in dihyropyrimidine dehydrogenase (DPD) to 5-fluorouracil toxicity. A single point mutation at a splice site causes skipping of an exon, deletion of 55 amino acids and an inactive protein. Additional mutant alleles have now been linked to inheritance of DPD deficiency.
  CAS PubMed PubMed Central Google Scholar
• McLeod, H. L. et al. Nomenclature for human DPYD alleles. Pharmacogenetics 8, 455–459 (1998).
  CAS PubMed Google Scholar
• Hori, T. et al. Regional assignment of the human thymidylate synthase (TS) gene to chromosome band 18p11.32 by nonisotopic in situ hybridization. Hum. Genet. 85, 576–580 (1990).
  CAS PubMed Google Scholar
• Villafranca, E. et al. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J. Clin. Oncol. 19, 1779–1786 (2001).This study shows that a variable number of tandem repeats in the thymidylate synthase promoter is associated with response to 5-fluorouracil. It provides evidence for further incorporation of pharmacogenetics studies in cancer clinical trials.
  CAS PubMed Google Scholar
• Marsh, S., McKay, J. A., Cassidy, J. & McLeod, H. L. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int. J. Oncol. 19, 383–386 (2001).
  CAS PubMed Google Scholar
• Johnston, P. G. et al. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumours. Cancer Res. 55, 1407–1412 (1995).
  CAS PubMed Google Scholar
• Leichman, C. G. et al. Quantitation of intratumoural thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J. Clin. Oncol. 15, 3223–3229 (1997).
  CAS PubMed Google Scholar
• Kawakami, K., Omura, K., Kanehira, E. & Watanabe, Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 19, 3249–3252 (1999).
  CAS PubMed Google Scholar
• Horie, N., Aiba, H., Oguro, K., Hojo, H. & Takeishi, K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 20, 191–197 (1995).
  CAS PubMed Google Scholar
• Rougier, P. et al. Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352, 1407–1412 (1998).
  CAS PubMed Google Scholar
• Kudoh, S. et al. Phase II study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. West Japan Lung Cancer Group. J. Clin. Oncol. 16, 1068–1074 (1998).
  CAS PubMed Google Scholar
• Gupta, E. et al. Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. Cancer Res. 54, 3723–3725 (1994).
  CAS PubMed Google Scholar
• Kawato, Y., Aonuma, M., Hirota, Y., Kuga, H. & Sato, K. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumour effect of CPT-11. Cancer Res. 51, 4187–4191 (1991).
  CAS PubMed Google Scholar
• Bosma, P. J. et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N. Engl. J. Med. 333, 1171–1175 (1995).
  CAS PubMed Google Scholar
• Ando, Y. et al. Polymorphisms of UDP-glucuronosyl-transferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res. 60, 6921–6926 (2000).
  CAS PubMed Google Scholar
• Iyer, L. et al. Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J. Clin. Invest. 101, 847–854 (1998).The enzyme responsible for glucuronidation of the active metabolite of irinotecan was identified, and liver extracts taken from patients with an inherited deficiency in this enzyme were shown to be defective in this process. The Gunn rat model was used to confirm the role of the glucuronosyl-transferase.
  CAS PubMed PubMed Central Google Scholar
• Iyer, L. et al. Phenotype–genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin. Pharmacol. Ther. 65, 576–582 (1999).
  CAS PubMed Google Scholar
• Fisher, M. B. et al. Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. Pharmacogenetics 10, 727–739 (2000).
  CAS PubMed Google Scholar
• MacKenzie, P. I. et al. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7, 255–269 (1997).
  CAS PubMed Google Scholar
• Ritter, J. K. et al. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J. Biol. Chem. 267, 3257–3261 (1992).
  CAS PubMed Google Scholar
• Wasserman, E. et al. Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. Ann. Oncol. 8, 1049–1051 (1997).
  CAS PubMed Google Scholar
• Santos, A. et al. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin. Cancer Res. 6, 2012–2020 (2000).
  CAS PubMed Google Scholar
• Humerickhouse, R., Lohrbach, K., Li, L., Bosron, W. F. & Dolan, M. E. Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res. 60, 1189–1192 (2000).
  CAS PubMed Google Scholar
• Khanna, R., Morton, C. L., Danks, M. K. & Potter, P. M. Proficient metabolism of irinotecan by a human intestinal carboxylesterase. Cancer Res. 60, 4725–4728 (2000).
  CAS PubMed Google Scholar
• Sugatani, J. et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyl-transferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33, 1232–1238 (2001).
  CAS PubMed Google Scholar
• Gupta, E., Wang, X., Ramirez, J. & Ratain, M. J. Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother. Pharmacol. 39, 440–444 (1997).
  CAS PubMed Google Scholar
• Tew, K. D. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res. 54, 4313–4320 (1994).
  CAS PubMed Google Scholar
• Ketterer, B. Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat. Res. 202, 343–361 (1988).
  CAS PubMed Google Scholar
• Nebert, D. W., McKinnon, R. A. & Puga, A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol. 15, 273–280 (1996).
  CAS PubMed Google Scholar
• Woo, M. H. et al. Glutathione _S_-transferase genotypes in children who develop treatment-related acute myeloid malignancies. Leukemia 14, 226–231 (2000).
  Google Scholar
• Chen, H. et al. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase θ 1 (GSTT1) gene defect. Lancet 347, 295–297 (1996).
  CAS PubMed Google Scholar
• Seidegard, J. & Ekstrom, G. The role of human glutathione transferases and epoxide hydrolases in the metabolism of xenobiotics. Environ. Health Perspect. 105, 791–799 (1997).
  CAS PubMed PubMed Central Google Scholar
• Chen, C.-L., Liu, Q. & Relling, M. V. Simultaneous characterization of glutathione _S_-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks. Pharmacogenetics 6, 187–191 (1996).
  CAS PubMed Google Scholar
• Hayes, J. D. & Strange, R. C. Potential contribution of the glutathione _S_-transferase supergene family to resistance to oxidative stress. Free Radic. Res. 22, 193–207 (1995).
  CAS PubMed Google Scholar
• Ban, N. et al. Transfection of glutathione _S_-transferase (GST)-π antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide. Cancer Res. 56, 3577–3582 (1996).
  CAS PubMed Google Scholar
• Stanulla, M., Schrappe, M., Brechlin, A. M., Zimmermann, M. & Welte, K. Polymorphisms within glutathione _S_-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study. Blood 95, 1222–1228 (2000).
  CAS PubMed Google Scholar
• Chen, C.-L. et al. Higher frequency of glutathione _S_-transferase deletions in black children with acute lymphoblastic leukemia. Blood 89, 1701–1707 (1997).
  CAS PubMed Google Scholar
• Anderer, G. et al. Polymorphisms within glutathione _S_-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics 10, 715–726 (2000).
  CAS PubMed Google Scholar
• Sweeney, C. et al. Association between survival after treatment for breast cancer and glutathione _S_-transferase P1 Ile105Val polymorphism. Cancer Res. 60, 5621–5624 (2000).
  CAS PubMed Google Scholar
• Davies, S. M. et al. Glutathione _S_-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia. J. Clin. Oncol. 19, 1279–1287 (2001).A randomized trial showed that intensive chemotherapy was more effective than conventionally administered chemotherapy. However, this study demonstrates that the benefit of the intensive schedule depends on polymorphisms in genes that encode glutathione transferase.
  PubMed Google Scholar
• Chabner, B. A., Donehower, C. & Schilsky, R. L. Clinical pharmacology of methotrexate. Cancer Treat. Rep. 65, 51–54 (1981).
  PubMed Google Scholar
• Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 10, 111–113 (1995).A common point mutation affects the stability of methylene tetrahydrofolate reductase, an enzyme that regulates folate and homocysteine metabolism. Individuals homozygous for the mutation have significantly elevated plasma homocysteine levels and an increased risk of developing vascular disease. The mutation was subsequently shown to affect response to drugs such as methotrexate, and to increase the risk for congenital diseases such as spina bifida.
  CAS PubMed Google Scholar
• Goyette, P. et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genet. 7, 195–200 (1994).
  CAS PubMed Google Scholar
• Ulrich, C. M. et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98, 231–234 (2001).
  CAS PubMed Google Scholar
• Molloy, A. M. et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349, 1591–1593 (1997).
  CAS PubMed Google Scholar
• Jacques, P. F., Selhub, J., Bostom, A. G., Wilson, P. W. & Rosenberg, I. H. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 340, 1449–1454 (1999).
  CAS PubMed Google Scholar
• Gorlick, R. et al. Intrinsic and acquired resistance to methotrexate in acute leukemia. N. Engl. J. Med. 335, 1041–1048 (1996).
  CAS PubMed Google Scholar
• Jansen, G. et al. A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. J. Biol. Chem. 273, 30189–30198 (1998).
  CAS PubMed Google Scholar
• Wong, S. C. et al. Impaired membrane transport in methotrexate-resistant CCRF-CEM cells involves early translation termination and increased turnover of a mutant reduced folate carrier. J. Biol. Chem. 274, 10388–10394 (1999).
  CAS PubMed Google Scholar
• Chango, A. et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab. 70, 310–315 (2000).
  CAS PubMed Google Scholar
• Carman, M. D. et al. Resistance to methotrexate due to gene amplification in a patient with acute leukemia. J. Clin. Oncol. 2, 16–20 (1984).
  CAS PubMed Google Scholar
• Goto, Y. et al. A novel single-nucleotide polymorphism in the 3′-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin. Cancer Res. 7, 1952–1956 (2001).
  CAS PubMed Google Scholar
• Gonzalez, F. J. Evolution of the P450 gene superfamily: animal–plant 'warfare', molecular drive and human genetic differences in drug oxidation. Trends. Genet. 6, 182–186 (1990).
  CAS PubMed Google Scholar
• Haiman, C. A., Hankinson, S. E., Colditz, G. A., Hunter, D. J. & De Vivo, I. A polymorphism in CYP17 and endometrial cancer risk. Cancer Res. 61, 3955–3960 (2001).
  CAS PubMed Google Scholar
• McKean-Cowdin, R. et al. Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype. Cancer Res. 61, 848–849 (2001).
  CAS PubMed Google Scholar
• Chang, T. K., Yu, L., Maurel, P. & Waxman, D. J. Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 57, 1946–1954 (1997).
  CAS PubMed Google Scholar
• Kivisto, K. T., Kroemer, H. K. & Eichelbaum, M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br. J. Clin. Pharmacol. 40, 523–530 (1995).
  CAS PubMed PubMed Central Google Scholar
• Relling, M. V. Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs? Ther. Drug Monit. 18, 350–356 (1996).
  CAS PubMed Google Scholar
• Kuehl, P. et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet. 27, 383–391 (2001).Although it had been known for many years that CYP3A5 is expressed in only 20–50% of human livers, this is the first elucidation of the molecular basis for variation in expression. The mechanism involves the common occurrance of a point mutation that results in alternative exon splicing and introduction of a stop codon.
  CAS PubMed Google Scholar
• Paulussen, A. et al. Two linked mutations in transcriptional regulatory elements of the CYP3A5 gene constitute the major genetic determinant of polymorphic activity in humans. Pharmacogenetics 10, 415–424 (2000).
  CAS PubMed Google Scholar
• Sata, F. et al. CYP3A4 allelic variants with amino acid substitutions in exon 7 and 12: Evidence for an allelic variant with altered catalytic activity. Clin. Pharmacol. Ther. 67, 48–56 (2000).
  CAS PubMed Google Scholar
• Ball, S. E. et al. Population distribution and effects on drug metabolism of a genetic variant in the 5′ promoter region of CYP3A4. Clin. Pharmacol. Ther. 66, 288–294 (1999).
  CAS PubMed Google Scholar
• Rebbeck, T. R., Jaffe, J. M., Walker, A. H., Wein, A. J. & Malkowicz, S. B. Modification of clinical presentation of prostate tumours by a novel genetic variant in CYP3A4. J. Natl Cancer Inst. 90, 1225–1229 (1998).
  CAS PubMed Google Scholar
• Borst, P., Evers, R., Kool, M. & Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl Cancer Inst. 92, 1295–1302 (2000).
  CAS PubMed Google Scholar
• Norris, M. D. et al. Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma. N. Engl. J. Med. 334, 231–238 (1996).
  CAS PubMed Google Scholar
• Sullivan, G. F. et al. Regulation of expression of the multidrug resistance protein MRP1 by p53 in human prostate cancer cells. J. Clin. Invest. 105, 1261–1267 (2000).
  CAS PubMed PubMed Central Google Scholar
• Pirker, R. et al. MDR1 gene expression and treatment outcome in acute myeloid leukemia. J. Natl Cancer Inst. 83, 708–712 (1991).
  CAS PubMed Google Scholar
• Ameyaw, M. M. et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11, 217–221 (2001).
  CAS PubMed Google Scholar
• Ito, S. et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 11, 175–184 (2001).
  CAS PubMed Google Scholar
• Hoffmeyer, S. et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA 97, 3473–3478 (2000).
  CAS PubMed PubMed Central Google Scholar
• Heuvel-Eibrink, M. M. et al. MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia. Blood 97, 3605–3611 (2001).
  PubMed Google Scholar
• Carling, T., Rastad, J., Akerstrom, G. & Westin, G. Vitamin D receptor (VDR) and parathyroid hormone messenger ribonucleic acid levels correspond to polymorphic VDR alleles in human parathyroid tumours. J. Clin. Endocrinol. Metab. 83, 2255–2259 (1998).
  CAS PubMed Google Scholar
• Ho, Y. V. et al. Polymorphism of the vitamin D receptor gene and corticosteroid-related osteoporosis. Osteoporos. Int. 9, 134–138 (1999).
  CAS PubMed Google Scholar
• Huizenga, N. A. et al. A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J. Clin. Endocrinol. Metab 83, 144–151 (1998).
  CAS PubMed Google Scholar
• Roden, D. M. Taking the 'idio' out of 'idiosyncratic': predicting torsades de pointes. Pacing Clin. Electrophysiol. 21, 1029–1034 (1998).
  CAS PubMed Google Scholar
• Priori, S. G. et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation 99, 674–681 (1999).
  CAS PubMed Google Scholar
• Rietschel, M. et al. Dopamine D3 receptor variant and tardive dyskinesia. Eur. Arch. Psychiatry Clin. Neurosci. 250, 31–35 (2000).
  CAS PubMed Google Scholar
• Liggett, S. B. β2-Adrenergic receptor pharmacogenetics. Am. J. Respir. Crit. Care Med. 161, 197–201 (2000)
  Google Scholar
• Arranz, M. J. et al. Pharmacogenetic prediction of clozapine response. Lancet 355, 1615–1616 (2000).Showed that up to 75% of the variation in the schizophrenia patients' response to the antipsychotic drug clozapine could be accounted for by just six genetic polymorphisms. This is a good example of how multiple polymorphisms in a relatively large population can be used to determine a complex drug response phenotype.
  CAS PubMed Google Scholar
• O'Toole, L., Stewart, M., Padfield, P. & Channer, K. Effect of the insertion/deletion polymorphism of the angiotensin-converting enzyme gene on response to angiotensin-converting enzyme inhibitors in patients with heart failure. J. Cardiovasc. Pharm. 32, 988–994 (1998).
  CAS Google Scholar
• Martinelli, I. et al. High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives. N. Engl. J. Med. 338, 1793–1797 (1998).
  CAS PubMed Google Scholar
• Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
  CAS PubMed Google Scholar
• Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).
  CAS PubMed Google Scholar
• Kwok, P. Y. High-throughput genotyping assay approaches. Pharmacogenomics 1, 95–100 (2000).
  CAS PubMed Google Scholar
• Klausner, R. D. The future of cancer research and the role of the National Cancer Institute. J. Clin. Oncol. 14, 2878–2883 (1996).
  CAS PubMed Google Scholar
• Thomas, D. C. Design of gene characterization studies: an overview. J. Natl Cancer Inst. Monogr. 17–23 (1999).
• Spurdle, A. B. et al. CYP17 promoter polymorphism and breast cancer in Australian women under age forty years. J. Natl Cancer Inst. 92, 1674–1681 (2000).
  CAS PubMed Google Scholar
• Mahgoub, A., Idle, J. R., Dring, L. G., Lancaster, R. & Smith, R. L. Polymorphic hydroxylation of debrisoquire in man. Lancet 2, 584–586 (1977).
  CAS PubMed Google Scholar