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

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 (Cl): 1.18-120.56; P= 0.04]. Furthermore, patients heterozygous for the ALDH1A1*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 ALDH1A1 *2 allele have an increased risk of haemorrhagic 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 Genomics 18:1009-1015