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


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 involvedin drug disposition can influence therapeutic outcome. The homozygous null deletion of phase II metabolicgene 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 thecellular level of free radicals may have important roles in generating drug- related adverse effects. We hereinvestigated the null polymorphism of GSTT1, and the -463G>A promoter polymorphism of oxidative stressgene myeloperoxidase (MPO) for carboplatin toxicity in a population of northern India. Cancer patients whowere treated with carboplatin, and developed toxicity was considered. The study group comprised of 10 patientswho 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 PCRfollowed by RFLP. Hematologic toxicity was experienced by 5 patients, 2 of them had grade 3 and 4 toxicity and3 others had grade 2 toxicity. They also had gastrointestinal (GI) toxicity. Remaining 5 individuals developedGI toxicity but no hematological toxicity. While GG homozygous of MPO was present in majority of patientshaving hematologic toxicity (in 4 out of 5 individuals), one A allele (AG genotype) was present in 4 patientswho did not have any hematological toxicity. Thus variant A allele of MPO -463G>A may be related to lowerhematological toxicity. These preliminary data, however, are required to be confirmed in larger studies alongwith other relevant polymorphisms.