Relations between polymorphisms in drug-metabolising enzymes and toxicity of chemotherapy with cyclophosphamide, thiotepa and carboplatin

C Ekhart, S. Rodenhuis, P.H.M. Smits, J.H. Beijnen, A.D.R. Hultema

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose High-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTC) has been developed as a possible curative treatment modality in several solid tumours. However, a large interindividual variability in toxicity is encountered in high-dose chemotherapy. A priori identification of patients at risk for toxicity could be an attractive prospect. Genotyping of genes encoding drug-metabolising enzymes might provide such a tool. Experimental design We assessed 16 selected polymorphisms in nine genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) of putative relevance in CTC metabolism using polymerase chain reaction and DNA sequencing in 113 patients who were treated with high-dose chemotherapy regimens based on CTC. Results Patients heterozygous for the ALDH3A1*2 allele (allelic frequency 21.2%) had an increased risk of haemorrhagic cystitis when compared with patients with wild-type alleles [5/38 vs. 1/70; odds ratio (OR): 11.95, 95% confidence interval (CI): 1.18-120.56; P=0.04]. Furthermore, patients heterozygous for the ALDH1Al*2 allele (allelic frequency 5.8%) had an increased risk of liver toxicity when compared with patients with wild-type alleles (6/13 vs. 19/99; OR: 5.13,95% Cl: 1.30-20.30; P=0.02). No other relations reached significance. Conclusion Patients heterozygous for the ALDH3A1*2 and ALDH1Al*2 allele have an increased risk of haernorrhagic cystitis and liver toxicity, respectively, compared with patients with wild-type alleles when treated with a high-dose chemotherapy combination of CTC. Pharmacogenetic approaches can identify patients who are at risk of experiencing toxic side effects in high-dose chemotherapy. Pharmacogenetics and Genornics 18:1009-1015 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Original languageUndefined/Unknown
Pages (from-to)1009-1015
Number of pages7
JournalPharmacogenetics and Genomics
Volume18
Issue number11
Publication statusPublished - 2008

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