Abstract
Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST enzymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion: The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.
Highlights
Cyclophosphamide is an alkylating agent with anticancer activity and used in the treatment of several neoplastic disorders such as multiple myeloma, leukemias, nonhodgkin lymphoma, breast and ovarian cancer
The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST enzymes are involved in detoxification
The aim of this study is to investigate the impact of the CYP2B6 single nucleotide polymorphisms (SNPs) as well as GSTM1, GSTT1 and GSTP1 polymorphisms on the outcome for multiple myeloma patients treated with cyclophosphamide
Summary
Cyclophosphamide is an alkylating agent with anticancer activity and used in the treatment of several neoplastic disorders such as multiple myeloma, leukemias, nonhodgkin lymphoma, breast and ovarian cancer. MM accounts for approximately 2% of all cancer deaths and 20% of deaths caused by haematological malignancies [1] Alkylating agents, such as melphalan and cyclophosphamide, together with corticosteroids and autologous stem cell transplantation (ASCT), is an effective conventional treatment [2]. The so-called novel agents, proteasome inhibitors and IMiDs (immunomodulatory drugs) used in the treatment of MM (bortezomib, thalidomide and lenalidomide) has been established and improved the outcome of these patients. In spite of this progress, almost all patients treated with ASCT relapse due to residual disease [3]. A fraction of patients have become long-term survivors after treatment with alkylating agents and better assessment for applying current treatment modalities is required in order to understand the nature of different responses to the therapy
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