Review
Update on pharmacogenetics in cancer chemotherapy

https://doi.org/10.1016/S0959-8049(01)00434-8Get rights and content

Abstract

This review describes how genetic differences among patients may change the therapeutic outcome in cancer chemotherapy. Severe toxicity in genetically predisposed patients is predominantly associated with mutations in drug metabolism enzyme genes, and an update on genetic intolerance to 6-mercaptopurine, 5-fluorouracil, and irinotecan is provided. Moreover, recent findings pointed out that the methylenetetrahydrofolate reductase (MTHFR) C677T mutation might change patient susceptibility to the toxic effects of the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen and raltitrexed. Finally, it is emerging that not only toxicity, but also response to chemotherapy could be influenced by pharmacogenetic determinants, and the clinical relevance of polymorphisms in thymidylate synthase (TS) and glutathione-S-transferase (GST) genes is discussed.

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 (www.pharmacogenetics.org) article was supported by a grant GM61393 from the National Institute of Health, Bethesda, MD, USA.

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