ReviewUpdate on pharmacogenetics in cancer chemotherapy
Introduction
The role of pharmacogenetics in cancer chemotherapy is progressively changing. Besides the “classical” examples of reduced tolerance to chemotherapy, genetic determinants might also affect patients' response and survival. Genotypic stratification of patients might identify subgroups with a better prognostic profile. The presence of alleles associated with reduced responsiveness to a certain drug might guide the selection of alternative therapies.
The need for optimisation in cancer chemotherapy is urgent. Adjusting the dose by body surface area does not correct for inter-individual differences in drug disposition. The intrinsic potency of cytotoxic agents and their use at maximally tolerated doses render chemotherapeutic treatment a high risk procedure for those patients that deviate from the average population. Identifying the genetic reasons behind either the occurrence of toxicity or lack of tumour response will reduce the unpredictability of cancer treatment. This review highlights the most recent findings on pharmacogenetic correlations between toxicity/response and mutated genetic traits.
Section snippets
6-Mercaptopurine and thiopurine methyltransferase pharmacogenetics
Mutations in the thiopurine methyltransferase (TPMT) gene have profound effects on 6-mercaptopurine (6-MP) tolerance and dose intensity in maintenance treatment of acute lymphoblastic leukaemia (ALL) in children 3, 4. A recent trial estimated that 71% of patients with bone marrow intolerance to 6-MP were phenotypically-TPMT deficient [5]. When 14 of these patients were typed for open reading frame (ORF) mutations associated with TPMT deficiency (TPMT*2, TPMT*3A, TPMT*3C (Table 1), 9 of them
Thymidylate synthase pharmacogenetics in colorectal cancer patients
Acute induction of TS has been associated with resistance to fluoropyrimidine derivatives 35, 36, and tumour TS expression is inversely related to clinical response 37, 38, 39. In the TS enhancer region, two, three, four and nine copies of 28-bp tandem repeated sequences (TSER*2, TSER*3, TSER*4, TSER*9) have been described 40, 41, 42. TS expression was increased by 2.6-fold when the triple repeat was compared with the double repeat in transient expression assays [40], and a similar trend was
Conclusions
The availability of potent and reliable genetic techniques can change the way patients will receive chemotherapy in the near future. With this perspective in mind, oncologists and clinical pharmacologists should prompt the inclusion of pharmacogenetic investigation and DNA collection into early phases of clinical drug development.
How to recognise the possible presence of a pharmacogenetic issue in cancer patients under chemotherapy treatment? If highly variable or bimodal pharmacokinetics are
Acknowledgements
This Pharmacogenetics of Anticancer Agents Research Group () article was supported by a grant GM61393 from the National Institute of Health, Bethesda, MD, USA.
References (59)
- et al.
Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia
Blood
(1999) - et al.
Genetic variation in bilirubin UDP-glycuronyltransferase gene promoter and Gilbert's syndrome
Lancet
(1996) - et al.
The genetic basis of Gilbert's syndrome
Lancet
(1996) - et al.
MTHFR gene polymorphism and severe toxicity during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil (CMF)
Ann. Oncol.
(2000) - et al.
A common methylenetetrahydrofolate reductase gene mutation and longevity
Atherosclerosis
(1998) - et al.
Biological and clinical implications of the MTHFR C677T polymorphism
Trends Pharmacol. Sci.
(2001) - et al.
Novel thymidylate synthase enhancer region alleles in African populations
Hum. Mutat.
(2000) - et al.
Glutathione-S-transferase family of enzymes
Mutat. Res.
(2001) - et al.
Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemiaa case-control study
Blood
(2000) - et al.
Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia
Blood
(1997)
Pharmacogeneticsa tool for individualizing antineoplastic therapy
Clin. Pharmacokinet.
Pharmacogenetics of anticancer agentslessons from amonafide and irinotecan
Drug Metab. Dispos.
Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia
Br. J. Haematol.
Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus
J. Natl. Cancer Inst.
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine
J. Clin. Oncol.
Segregation analysis of human red blood cell thiopurine methyltransferase activity
Genet. Epidemiol.
Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library
Pharm. Res.
Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population
Br. J. Pharmacol.
Characterization of a variable number tandem repeat region in the thiopurine S-methyltransferase gene promoter
Pharmacogenetics
Influence of the variable number of tandem repeats located in the promoter region of the thiopurine methyltransferase gene on enzymatic activity
Clin. Pharmacol. Ther.
Thiopurine methyltransferase polymorphic tandem repeatgenotype-phenotype correlation analysis
Clin. Pharmacol. Ther.
Genomic structure and multiple single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene
J. Hum. Genet.
Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liverpopulation characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy
Cancer Res.
Dihydropyrimidine dehydrogenase deficiency and fluorouracil-related toxicity
Br. J. Cancer
Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicityidentification of new mutations in the DPD gene
Clin. Cancer Res.
Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracilfrequency of the common IVS14+1G>A mutation causing DPD deficiency
Clin Cancer Res.
Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5′-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)—related toxicity compared with controls
Clin. Cancer Res.
Known variant DPYD alleles do not explain DPD deficiency in cancer patients
Pharmacogenetics
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