Polymorphisms GSTT1, GSTM1 and GSTP1 influence in magnitude of DNA damage induced by cyclophosphamide

Abstract

Cancer is one of the major causes of death worldwide and one of the factors associated with this is the therapeutic failure. Recently there has been an increasing interest in designing personalized therapies based on patient’s genotype. Glutathione–S-Transferase genes GSTT1, GSTM1 and GSTP1 genes help in detoxification of various genotoxic agents such as cyclophosphamide, an indirect alkylating agent that damages the chemical structure of DNA. It is widely used with other drugs in the treatment of various cancers. Determine whether the extent of DNA damageevaluated by the comet assay performed in vitro by cyclophosphamide in lymphocytes is modulated by polymorphisms of GSTT1, GSTM1 and GSTP1. Lymphocytes from 120 healthy donors were treated with a single concentration of cyclophosphamide and the extent of DNA damage was evaluated by a modified comet assay. Polymorphisms of GSTT1 and GSTM1 were identified by end-point polymerase chain reaction, while GSTP1 alleles were identified by PCR-RFLP. A great variability in the response to cyclophosphamide was found among individuals. Only 12 individuals from all the volunteer donors showed to have the complete wild genotype (GSTT1, GSTM1, GSTP1Ile/Ile105, Ala/Ala114) and coincidentally, this was the group with the lowest cyclophosphamide produced DNA damage