Polymorphisms at GSTM1 and GSTP1 gene loci and risk of prostate cancer in a South Indian population.

Inter-individual differences in cancer susceptibility may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S-transferases (GSTs), which are active in detoxification of wide variety of carcinogens, have been consistently implicated as cancer susceptibility genes in this context. We here assessed the association of GSTM1 and GSTP1 polymorphisms with susceptibility to prostate cancer in a case-control study of 75 patients and 100 age-matched controls in a South Indian population. The GSTM1 null polymorphism was detected by PCR and the GSTP1 Ile105Val polymorphism by PCR-RFLP using peripheral blood DNA. There was no significant link between the null genotype of GSTM1 and risk of prostate cancer (OR-1.79; 95% CI-0.78-4.11; P-0.18). However, the GSTP1 Ile/Val genotype was significantly associated with a decreased risk for prostate cancer (OR-0.36; 95% CI-0.18-0.73; P<0.001). Analysis of the variant GSTM1 and GSTP1 genotypes in combination did not reveal any significant difference between cases and controls, even with a stratified analysis tumor grades. Thus our study indicates that the GSTP1 Ile/Val genotype may decrease risk of prostate cancer in the South Indian population.

Modification of 2-deoxy-D-glucose on radiation-and chemotherapeutic drug-induced chromosomal aberrations.

BACKGROUND: Chemotherapy is the treatment of cancer with drugs, often used as either adjuvant or neoadjuvant or in conjunction with radiation and surgery. Unfortunately, majority of the drugs are toxic to normal tissues, the toxicity being resulting from multidrug protocol used to induce remissions and achieve tumor care. While it has been demonstrated for compounds like the 2-deoxy-glucose (2-DG) used as a modulator for radiation-induced damages, such studies were rarely reported for chemotherapeutic drugs. OBJECTIVE: To study the effect of 2-DG on radiation-and chemotherapeutic drug-induced chromosomal aberrations in normal and tumor cells exposed in vitro. MATERIALS AND METHODS: The peripheral blood lymphocytes (PBLs) and BMG-1 cells were exposed to radiation and chemotherapeutic drugs (bleomycin and mitomycin-C) in the presence and absence of 2-DG. The treated cells were cultured for various durations, arrested at either metaphase or cytokinesis stage of the cell cycle. The stable and unstable aberrations were recorded using Giemsa staining and FISH technique. The cell cycle kinetics was studied using fluorescence plus Giemsa (FPG) staining. RESULTS: The presence of 2-DG reduced stable and unstable chromosome aberrations (CA) significantly (P < 0.001), in PBLs induced by radiation, bleomycin and mitomycin-C, when compared to cells treated with radiation or the drugs and increased significantly in BMG cells (P < 0.001). Furthermore, the presence of 2-DG altered the cell cycle kinetics in the PBLs and BMG-1 cells. Thus the overall results showed protection effect on the normal cell damages induced by radiation and chemotherapeutic drugs, while sensitizes the tumor cell. CONCLUSION: The obtained results suggest that 2-DG in combination with radiotherapy/chemotherapy could lead to an improvement in tumor therapy by sensitizing the tumor cells while protecting the normal cells.

South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer.

The androgen receptor (AR) gene possesses polymorphic CAG tandem repeats and the repeat length has been inversely related to the risk of prostate cancer (PCa). The distinct ethnic variation in the CAG repeat length may be correlated to differences in PCa risk in different populations. To evaluate the CAG repeat length in the AR gene and the implications for PCa, we screened 87 PCa patients and 120 control subjects from South India. The mean CAG repeat length in PCa patients was significantly smaller than that of controls (17.0 vs 20.7; P < 0.001). Men with < or = 19 CAG repeats had a significantly increased risk of cancer compared to those with >19 CAG repeats (age-adjusted OR = 7.01; 95% CI = 3.52-13.94; P < 0.001). However, no significant association was observed between CAG repeats and age of onset or prostate-specific antigen levels. Although there was a trend towards shorter CAG repeat length in high grades of cancer, it was not significant (P = 0.085). Thus, our results suggest an association between short CAG repeats in the AR gene and PCa risk in South Indian men. Further, we propose that CAG repeats could be used as a prognostic marker for PCa diagnosis.

Cytochrome p4501A1 gene variants as susceptibility marker for prostate cancer.

CYP1A1 activates environmental procarcinogens and catalyzes oxidative metabolism of estrogens and is likely to play an important role in the etiology of prostate cancer. To evaluate this phenomenon, the association between two single nucleotide polymorphisms (A to G transition in exon7 leading to amino acid substitution Ile462Val and T3801C at 3'UTR) of CYP1A1 gene in prostate cancer were analyzed in a case-control study of 100 individuals in South Indian population. The estimated relative risk was significantly high for individuals with w1/m1 genotype at 3'UTR of CYP1A1 gene (OR-4.64; 95%CI = 1.51-14.86; P < 0.01) whereas the CYP1A1 Ile/Val genotype (w2/m2) on exon 7 was found to be associated with a decreased risk for prostate cancer (OR-0.17; 95%CI = 0.02-0.89; P=0.03). A Stratified analysis of the genotypes with age of onset and tumor grade showed the w1/m1 genotype to be significantly associated with an early age of onset; however the tumor grades did not have significant association with the variant genotypes. Thus the present study indicates that individuals with the variant w1/m1 genotype exhibit an increased risk while those with w2/m2 genotype exhibit a decreased risk for prostate cancer.