Influence of Genetic Polymorphisms in CYP2C8 and ABCB1 on the Mobilization Ability and Toxicity of Paclitaxel,

We and others have described the efficacy of paclitaxel-based chemotherapy in mobilizing large amounts of hematopoietic progenitors (HP) both in patients with solid tumors,(Bone Marrow Transplant 2000;25:231–5), and with hematological malignancies (Haematologica 2008; 93:161–3). Like most drugs, the taxanes are not controlled by the actions of one gene, but believed to be dependent on several polymorphic proteins. Single nucleotide polymorphisms (SNPs) in the ABCB1 gene, which encodes the transport protein P-glycoprotein, or in in metabolic enzymes, such as CYP2C8, have been suggested to influence the pharmacokinetics and clinical response to paclitaxel. Aim. To retrospectively evaluate the effects of five known allelic variants in the CYP2C8, and ABCB1genes on the mobilization ability and toxicity of the anticancer agent paclitaxel. Patients and Methods. 107 patients with hematological malignancies (43 lymphoma, 41 myeloma, 23 acute leukemia) received paclitaxel 170 mg/m2 i.v. by continuous infusion for 24 hours (day 1) followed by 8 mg/kg s.c G-CSF daily until the last apheresis. 77% received this treatment after failure of mobilization with G-CSF, and the rest as first line therapy because of risk factors for failure to achieve successful mobilization. The genetic variants (ABCB1 rs1045642 A >G, ABCB1 rs2032582 C>A, ABCB1 rs2032582 C>T, CYP2C8 rs10509681 C>T, and CYP2C8 rs11572080 A>G), were genotyped by allelic discrimination polymerase chain reaction (PCR) assays using TaqMan®Genotyping Assays (Applied Biosystems). The effect of genotypes on mobilization efficacy and on maximal hematological toxicity (according to the NCI version 3) was retrospectively assessed. Results. Allelic frequencies for rs1045642 A>G, rs2032582 C>A, rs2032582 C>T, rs10509681 C>T, and rs11572080 A>G variants, were 0.46, 0.40, 0.8, 0.13, and 0.13, respectively. Successful mobilization (>2 10⁶/kg CD34+ cells) was achieved in 57% of patients. No reproducible significant associations between genotype and outcome (evaluated as number of CD34+ cells/kg in the first and total apheresis, number of collections performed, and on the mobilization success [p>0.05]), nor on myeloid or platelet toxicity (p>0.05) were found for any of the SNPs analyzed. Discussion. This study on a well-defined patient population suggests that the presently evaluated variant alleles in CYP2C8 and ABCB1 genes do not explain the substantial interindividual variability in the outcome or hematological toxicity of the mobilization schedule using paclitaxel and G-CSF. Funding. This study was supported in part by a research grants 04515/GERM/06; RECAVA RD06/0014/0039, and FIS 10/02594.

No relevant conflicts of interest to declare.