The influence of glutathion S-transferase P-1 polymorphism A313G rs1695 on the susceptibility to cyclophosphamide hematologic toxicity in Indonesian patients
Abstract
Background: Chemotherapy often causes side effects such as hematologic toxicity. The degree of toxicity is often associated with genetic polymorphism. This study aims to determine the influence of GSTP1 A313G polymorphism, an enzyme responsible for detoxifying cyclophosphamid, on incidence and severity of cyclophosphamid hematologic toxicity.
Methods: 91 Indonesian females diagnosed with breast cancer at Haji Adam Malik Central General Hospital, Medan, receiving cyclophosphamide, doxorubicin/epirubicin and 5-FU were included in this retrospective cohort study. DNA was extracted from peripheral leukocytes and GSTP1 A313G genotyping was analyzed using polymerase chain reaction-restriction length fragment polymorphism (PCR-RFLP). Genotype deviation and allele frequencies were also determined by Hardy-Weinberg Equilibrium. The degrees of hematologic toxicity (leucopenia and neutropenia data after chemotherapy cycles 1 and 3) were collected from the patient medical records. The data were analyzed using chi-square test.
Results: 60.4% of the patients had the wildtype (A/A), while 29.7% were heterozygous (A/G), and 9.9% were homozygous mutant (G/G). There was no significant deviation of allele and genotype frequency from Hardy-Weinberg Equilibrium. The G allele (A/G & G/G) contributes to more severe degree of leukopenia compared to patients with wild type allele (A/A) (p<0.05) after the 3rd chemotherapy cycles.
Conclusion: There was association between GSTP1 polymorphism with the degree of hematologic toxicity in breast cancer patients receiving cyclophosphamide chemotherapy regimen.
References
Thirumaran R, Prendergast GC, Gilman PB. Cytotoxic chemotherapy in clinical treatment of cancer. In: Prendergast GC, Jaffee EM, editors. Cancer immunotherapy: immune suppresion and tumor growth. USA: Elsevier Inc; 2007. p. 101-16. http://dx.doi.org/10.1016/B978-012372551-6/50071-7
Daniel D, Crawford J. Myelotoxicity from chemotherapy. Semin Oncol. 2006 Nov;33(1):74-85. http://dx.doi.org/10.1053/j.seminoncol.2005.11.003
Zhang J, Tian Q, Zhou SF. Clinical pharmacology of cyclophosphamide and ifosfamide. Curr Drug Ther. 2006 Jan;1(1):55-84. http://dx.doi.org/10.2174/157488506775268515
Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM. The role of glutatione S-Transferase P in signalling pathways and S-glutathionylation in cancer. Free Radic Biol Med. 2011 July;51(2):299-313. http://dx.doi.org/10.1016/j.freeradbiomed.2011.04.013
Zhong SL, Zhou SF, Chen X, Chan SY, Chan E, Ng KY, et al. Relationship between genotype and enzyme activity of glutathione S-transferases M1 and P1 in Chinese. Eur J Pharm Sci. 2006 Jan;28(1-2):77-85. http://dx.doi.org/10.1016/j.ejps.2006.01.002
Zhang BL, Sun T, Zhang BN, Zheng S, Lü N, Xu BH, et al. Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer. Chin Med J. 2011 June;124(2):199-204. DOI: 10.3760/cma.j.issn.0366-6999.2011.02.008
Ge J, Tian A, Wang QS, Kong PZ, Yu Y, Li XQ, et al. The GSTP1 105Val allele increases breast cancer risk and aggressiveness but enhances response to cyclophosphamide chemotherapy in North China. PLoS One. 2013 June;8(6):e67589. http://dx.doi.org/10.1371/journal.pone.0067589
Tran A, Bournerias F, Le Beller C, Mir O, Rey E, Pons G, et al. Serious haematological toxicity of cyclophosphamide in relation to CYP2B6, GSTA1 and GSTP1 polymorphisms. Br J Clin Pharmacol. 2008 Sep;65(2):279-80. http://dx.doi.org/10.1111/j.1365-2125.2007.03020.x
Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD. Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide. Pharmacogenet Genomics. 2008 Feb;18(6):515-23. http://dx.doi.org/10.1097/FPC.0b013e3282fc9766
Artini IGA, Astuti I, Purwono S, Aryandono T. The association between glutathione S-Transferase P1 polymorphism and myelotoxicity in breast cancer patients receiving cyclophosphamide-contained chemotherapeutic regimen. Indones J Cancer. 2011 Sep;5(4):1-7.
Zhong S, Huang M, Yang X, Liang L, Wang Y, Romkes M, et al. Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophosphamide therapy in patients with systemic lupus erythematosus. Br J Clin Pharmacol. 2006 July;62(4):457-72. http://dx.doi.org/10.1111/j.1365-2125.2006.02690.x
ctep.cancer.gov [Internet]. Cancer therapy evaluation program: common terminology criteria for adverse events ( CTCAE ). [update 2006 August 9; cited 20 Jul 2012]. Available from: http://ctep.cancer.gov/.
Keswara MA, Sudarsa IW, Golden N. The risk factor of neutropenia on locally advanced breast cancer patients treated with first cycle cyclophosphamide, doxorubicine, 5- Fluorouracil chemotherapy at Sanglah General Hospital Denpasar, Bali-Indonesia. Bali Med J. 2012 Sep;1(3):116-20.
Han Y, Yu Z, Wen S, Zhang B, Cao X, Wang X. Prognostic value of chemotherapy-induced neutropenia in early-stage breast cancer. Breast Cancer Res Treat. 2012 Oct;131(2):483-90. http://dx.doi.org/10.1007/s10549-011-1799-1
Palappallil DS, Nair BL, Jayakumar KL, Puvathalil RT. Comparative study of the toxicity of 5-fluorouracil-adriamycin-cyclophosphamide versus adriamycin-cyclophosphamide followed by paclitaxel in carcinoma breast. Indian J Cancer. 2011 Jan;48(1):68-73. http://dx.doi.org/10.4103/0019-509X.75836
Balmukhanov TS, Khanseitova AK, Nigmatova VG, Ashirbekov EE, Talaeva SZ, Aitkhozhina NA. Polymorphisms at GSTM1, GSTP1, GSTT1 detoxification genes loci and risk of breast cancer in Kazakhstan population. Sci Res. 2013 Oct;2:114-8. http://dx.doi.org/10.4236/abcr.2013.24019
Huang MY, Wang YH, Chen FM, Lee SC, Fang WY, Cheng TL, et al. Multiple genetic polymorphisms of GSTP1 313AG, MDR1 3435CC, and MTHFR 677CC highly correlated with early relapse of breast cancer patients in Taiwan. Ann Surg Oncol. 2008 Jan;15(3):872-80. http://dx.doi.org/10.1245/s10434-007-9719-7
de Aguiar ES, Giacomazzi J, Schmidt AV, Bock H, Saraiva-Pereira ML, Schuler-Faccini L, et al. GSTM1, GSTT1, and GSTP1 polymorphisms, breast cancer risk factors and mammographic density in women submitted to breast cancer screening. Rev Bras Epidemiol. 2012;15(2):246-55. http://dx.doi.org/10.1590/S1415-790X2012000200002
Vivenza D, Feola M, Garrone O, Monteverde M, Merlano M, Lo Nigro C. Role of the renin-angiotensin-aldosterone system and the glutathione S-transferase Mu, Pi and Theta gene polymorphisms in cardiotoxicity after anthracycline chemotherapy for breast carcinoma. Int J Biol Markers. 2013 June;28(4):e336-47. http://dx.doi.org/10.5301/jbm.5000041
Ekhart C, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD. An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev. 2009 July;35(1):18-31. http://dx.doi.org/10.1016/j.ctrv.2008.07.003
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