GSTT1 null and MPO -463G>A Polymorphisms and Carboplatin Toxicity in an Indian Population

  • Bag, Arundhati (Institute of Allied Health (Paramedical) Services, Education and Training) ;
  • Pant, Nirdosh Kumar (Swami Ram Cancer Hospital and Research Center) ;
  • Jeena, Lalit Mohan (Institute of Allied Health (Paramedical) Services, Education and Training) ;
  • Bag, Niladri (Department of Plantation Management and Studies, Sikkim University) ;
  • Jyala, Narayan Singh (Department of Biochemistry, Govt. Medical College)
  • Published : 2013.08.30


Carboplatin, a second generation platinum drug, is widely used to treat different types of cancers. However, myelosuppression remains a major consideration in its use. Genetic polymorphisms of enzymes involved in drug disposition can influence therapeutic outcome. The homozygous null deletion of phase II metabolic gene GSTT1 that abolishes its xenobiotic- detoxifying ability may be associated with carboplatin toxicity. Further, since carboplatin generates oxidative stress, polymorphisms of oxidative stress genes that regulate the cellular level of free radicals may have important roles in generating drug- related adverse effects. We here investigated the null polymorphism of GSTT1, and the -463G>A promoter polymorphism of oxidative stress gene myeloperoxidase (MPO) for carboplatin toxicity in a population of northern India. Cancer patients who were treated with carboplatin, and developed toxicity was considered. The study group comprised of 10 patients who developed therapy- related adverse effects. Peripheral blood was taken from patients for DNA isolation. GSTT1 null genotype was determined by conducting duplex PCR and MPO-463 G>A was determined by PCR followed by RFLP. Hematologic toxicity was experienced by 5 patients, 2 of them had grade 3 and 4 toxicity and 3 others had grade 2 toxicity. They also had gastrointestinal (GI) toxicity. Remaining 5 individuals developed GI toxicity but no hematological toxicity. While GG homozygous of MPO was present in majority of patients having hematologic toxicity (in 4 out of 5 individuals), one A allele (AG genotype) was present in 4 patients who did not have any hematological toxicity. Thus variant A allele of MPO -463G>A may be related to lower hematological toxicity. These preliminary data, however, are required to be confirmed in larger studies along with other relevant polymorphisms.


  1. Bag A, Rawat S, Pant NK, et al (2012). Cancer patterns in Nainital and adjoining districts of Uttarakhand: A one year survey. J Nat Sci Biol Med, 3, 186-8.
  2. Bag A, Upadhyay S, Jeena LM, Pundir P, Jyala NS (2013). GSTT1 null genotype distribution in the Kumaun region of northern India. Asian Pac J Cancer Prev, 14, 87-9.
  3. Barahmani N, Carpentieri S, Li XN, et al (2009). Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma. Neuro Oncol, 11, 292-300.
  4. Cheng CF, Juan SH, Chen JJ, et al (2008). Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis. Apoptosis, 13, 883-94.
  5. Di Pietro G, Magno LAV, Rios-Santos F (2010) Glutathione S-transferases: an overview in cancer research. Expert Opin Drug Metab Toxicol, 6, 153-70.
  6. Donnelly JG (2004). Pharmacogenetics in cancer chemotherapy: balancing toxicity and response. Ther Drug Monit, 26, 231-5.
  7. Erculj N, Kovac V, Hmeljak J, Dolzan V (2012). The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma. Ann Oncol, 23, 961-7.
  8. Hayes JD, Pulford DJ (1995). The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol, 30, 445-600.
  9. He C, Tamimi RM, Hankinson SE, Hunter DJ, Han J (2009). A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk. Breast Cancer Res Treat, 113, 585-94.
  10. Husain K, Whitworth C, Somani SM, Rybak LP (2001). Carboplatin-induced oxidative stress in rat cochlea. Hear Res, 159, 14-22.
  11. Klebanoff SJ (1999). Myeloperoxidase. Proc Assoc Am Physicians, 111, 383-9.
  12. Lin H, Sue YM, Chou Y, et al (2010). Activation of a nuclear factor of activated T-lymphocyte-3 (NFAT3) by oxidative stress in carboplatin-mediated renal apoptosis. Br J Pharmacol, 161, 1661-76.
  13. Ma Q, Lu AY (2011) Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev, 63, 437-59.
  14. Marsh S, Paul J, King CR, et al (2007). Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish Randomised Trial in Ovarian Cancer. J Clin Oncol, 25, 4528-35.
  15. Millward MJ, Boyer MJ, Lehnert M, et al (2003). Docetaxel and carboplatin is an active regimen in advanced non-small-cell lung cancer: a phase II study in Caucasian and Asian patients. Ann Oncol, 14, 449-54.
  16. Moyer AM, Sun Z, Batzler AJ, et al (2010). Glutathione pathway genetic polymorphisms and lung cancer survival after platinum- based chemotherapy. Cancer Epidemiol Biomarkers Prev, 19, 811-21.
  17. Nakamura Y (2008). Pharmacogenomics and Drug Toxicity. N Engl J Med, 359, 856-8.
  18. O?dwyer PJ, Johnson SW, Hamilton TC (1997). Cisplatin and its analogues. In 'Cancer: Principles and Practices of oncology', Eds DeVita VT Jr., Hellman S, Rosenberg SA. Lippincott-Raven, Phila, 418-32.
  19. Ochoa L, Waypa G, Mahoney JR Jr, Rodriguez L, Minnear FL (1997). Contrasting effects of hypochlorous acid and hydrogen peroxide on endothelial permeability: prevention with cAMP drugs. Am J Respir Crit Care Med, 156, 1247-55.
  20. Palma JP, Aggarwal SK (1994). Cisplatin and carboplatin mediated release of cytolytic factors in murine peritoneal macrophages in vitro. Anticancer Drugs, 5, 615-22.
  21. Piedrafita FJ, Molander RB, Vansant G, et al (1996). An Alu element in the myeloperoxidase promoter contains a composite SP1- thyroid hormone-retinoic acid response element. J Biol Chem, 271, 14412-20.
  22. Sambrook J, Fritsch E, Maniatis T (1989). Molecular cloning- a laboratory manual. Cold Spring Harbor Laboratory Press, NY, 1989.
  23. Soo RA, Kawaguchi T, Loh M, et al (2012). Differences in outcome and toxicity between Asian and caucasian patients with lung cancer treated with systemic therapy. Future Oncol, 8, 451-62.
  24. Thorn CF, Ji Y, Weinshilboum RM, Altman RB, Klein TE (2012). PharmGKB summary: very important pharmacogene information for GSTT1. Pharmacogenet Genomics, 22, 646-51.
  25. Undevia SD, Gomez-Abuin G, Ratain MJ (2005). Pharmacokinetic variability of anticancer agents. Nat Rev Cancer, 5, 447-58.

Cited by

  1. Clinical Study on Carboplatin for Treating Pediatric Patients with Wilms Tumors vol.15, pp.17, 2014,