Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma

Zhou,Weiwei; An,Guangyu; Jian,Yuan; Guo,Huan; Chen,Wenming

doi:10.3892/ol.2015.3294

August-2015 Volume 10 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

August-2015 Volume 10 Issue 2

Full Size Image

Article

Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma

Authors:
- Weiwei Zhou
- Guangyu An
- Yuan Jian
- Huan Guo
- Wenming Chen
View Affiliations / Copyright

Affiliations: Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
Pages: 1171-1175
|
Published online on: May 29, 2015

https://doi.org/10.3892/ol.2015.3294
Expand metrics +

Abstract

Bortezomib is used to treat patients with multiple myeloma. It is primarily metabolized by the enzyme cytochrome P450 (CYP). Variations in the capacity of bortezomib metabolism affect the treatment outcomes and the side‑effects experienced by patients. In the present study, polymorphisms in the CYP3A4 and CYP2C19 genes were analyzed by polymerase chain reaction in 56 newly‑diagnosed patients with multiple myeloma. The polymorphisms analyzed included the c.681G>A, c.636G>A and c.-806C>T polymorphisms of CYP2C19. The CYP3A4 gene was sequenced after amplification and was classified into normal and mutant types. Associations between the metabolizer genotypes of CYP3A4 and CYP2C19, the therapeutic efficacy of bortezomib‑based regimens, and the occurrence of peripheral neuropathy were studied. The results identified no significant differences in gender, serum β2 microglobulin, creatinine, blood albumin, isotypes, and the Durie‑Salmon and International Staging System stages between the CYP2C19 poor + intermediate metabolizer types and the extensive + ultrarapid metabolizer types. In addition, it was revealed that the CYP2C19 and CYP3A4 phenotypes did not affect the efficacy of bortezomib‑based regimens, nor were they correlated with peripheral neuropathy. Additional large‑scale studies are required in order to evaluate the role of CYP enzymes in bortezomib treatments for patients with multiple myeloma.

View Figures

View References

1	Chen D, Frezza M, Schmitt S, Kanwar J and Dou QP: Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets. 11:239–253. 2011. View Article : Google Scholar : PubMed/NCBI
2	Kane RC, Bross PF, Farrell AT and Pazdur R: Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 8:508–513. 2003. View Article : Google Scholar : PubMed/NCBI
3	Iyer L and Ratain MJ: Pharmacogenetics and cancer chemotherapy. Eur J Cancer. 34:1493–1499. 1998. View Article : Google Scholar : PubMed/NCBI
4	Vangsted A, Klausen TW and Vogel U: Genetic variations in multiple myeloma II: association with effect of treatment. Eur J Haemotol. 88:93–117. 2012. View Article : Google Scholar
5	Uttamsingh V, Lu C, Miwa G and Gan LS: Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6 and 3A4, to the hepaticmetabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 33:1723–1728. 2005. View Article : Google Scholar : PubMed/NCBI
6	Timm R, Kaiser R, Lötsch J, et al: Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19. Pharmacogenomics J. 5:365–373. 2005. View Article : Google Scholar : PubMed/NCBI
7	Li Y, Hou J, Jiang H, et al: Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in multiple myeloma. Haematologica. 92:1246–1249. 2007. View Article : Google Scholar : PubMed/NCBI
8	Vangsted AJ, Søeby K, Klausen TW, et al: No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide and bortezomib in patients with multiple myeloma. BMC Cancer. 10:4042010. View Article : Google Scholar : PubMed/NCBI
9	Anderson KC, Bensinger W, Alsina M, et al: Multiple myeloma. In: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Version 1. 2013, http://www.nccn.org/professionals/physician_gls/f_guidelines.aspAccessed. March 12–2014
10	Durie BG, Harousseau JL, Miguel JS, et al International Myeloma Working Group: International uniform response criteria for multiple myeloma. Leukemia. 20:1467–1473. 2006. View Article : Google Scholar : PubMed/NCBI
11	The Human Cytochrome P450 (CYP) Allele Nomenclature Database. http://www.cypalleles.ki.se/Accessed. 20–Mar. 2014
12	Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW and Goldstein JA: Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 299:825–831. 2001.PubMed/NCBI
13	Kang YS, Park SY, Yim CH, et al: The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. Clin Pharmacol Ther. 85:312–318. 2009. View Article : Google Scholar : PubMed/NCBI
14	Lamba JK, Lin YS, Schuetz EG and Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 54:1271–1294. 2002. View Article : Google Scholar : PubMed/NCBI
15	Vangsted AJ, Klausen TW, Ruminski W, et al: The polymorphism IL-1beta T-31C is associated with a longer overall survival in patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant. 43:539–545. 2009. View Article : Google Scholar : PubMed/NCBI
16	Vangsted A, Gimsing P, Klausen TW, et al: Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation. Int J Cancer. 120:1036–1045. 2007. View Article : Google Scholar : PubMed/NCBI
17	Vangsted AJ, Klausen TW, Gimsing P, Andersen NF, Abildgaard N, Gregersen H and Vogel U: A polymorphism in NFKB1 is associated with improved effect of interferon-{alpha} maintenance treatment of patients with multiple myeloma after high-dose treatment with stem cell support. Haematologica. 94:1274–1281. 2009. View Article : Google Scholar : PubMed/NCBI
18	Badros A, Goloubeva O, Dalal JS, et al: Neurotoxicity of bortezomib therapy in multiple myeloma: a single-center experience and review of the literature. Cancer. 110:1042–1049. 2007. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Effect of CYP2C19 and CYP3A4 gene polymorphisms on the efficacy of bortezomib-based regimens in patients with multiple myeloma

This article is mentioned in:

Abstract

Related Articles