Author(s)

Ingrid Jakobsen Falk, Muhammad Suleman Khan, Lena Thunell, Hareth Nahi, Henrik Gréen

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Clinical Pharmacology, Division of Drug Research, Department of Medical and Health Sciences, Faculty of Health Sciences, Lin- k?pings Universitet, Link?ping, Sweden.

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.

Multiple Myeloma; Cyclophosphamide; CYP2B6; Glutathion-S-Transferases (GST); Single Nucleotide Polymorphisms; Pharmacogenetics; Pyrosequencing

I. Falk, M. Khan, L. Thunell, H. Nahi and H. Gréen, "Association of CYP2B6 Genotype with Survival and Progression Free Survival in Cyclophosphamide Treated Multiple Myeloma," Journal of Cancer Therapy, Vol. 3 No. 1, 2012, pp. 20-27. doi: 10.4236/jct.2012.31003.