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 £ 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.
Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD) when allowed to recover in their own spent medium. Addition of either insulin or insulin-like growth factor-1 (IGF-1) to the spent medium 60 to 120 min before irradiation significantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding) is reduced from 10.8 +/- 0.7 to 3.4 +/- 0.3 by insulin and to 3.0 +/- 0.4 by IGF-1. Neither growth factor alters the cell age distribution of the plateau-phase cells, increases the rate of incorporation of 5-bromo-2'-deoxyuridine into DNA, or alters the extent of radiation-induced mitotic delay in cells subcultured immediately after irradiation. Both insulin and IGF-1 alter the kinetics for rejoining of DNA double-strand breaks (DSBs), slowing the fast component of rejoining significantly. However, these growth factors have no effect on the initial level of DSBs or on the percentage of residual unrejoined breaks at 120 min postirradiation. Both growth factors affect repair of lesions leading to dicentric, but not to acentric, chromosome aberrations significantly. In control cells (treated with phosphate-buffered saline, 90 min prior to irradiation), the half-time for disappearance of dicentrics was 4.1 h (3.4 to 5.1 h), and 47.1 +/- 3.7% of the residual damage remained at 24 h postirradiation. Insulin and IGF-1 increased the half-time for disappearance of dicentrics to 5.2 h (3.9 to 7.7 h) and 5.7 h (5.5 to 5.9 h), respectively, and increased residual damage to 56.1 +/- 5.9% and 60.8 +/- 6.0%, respectively. Overall, these data show that insulin and IGF-1 inhibit PLD repair in A549 cells by mechanisms which are independent of changes in cell cycle parameters. The data suggest that the growth factors act by inducing changes in chromatin conformation which promote misrepair of radiation-damaged DNA.
Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD). Previously it was found that PLD repair could be partially inhibited by increasing the extracellular pH (pHe) of the spent medium from its normal value of 6.7-6.8 to 7.6 during postirradiation holding. The present study shows that PLD repair is also inhibited by reducing the pHe of the spent medium to 6.0. The effects of altering pHe on rejoining of DNA double-strand breaks (DSBs) as measured by neutral filter elution and on mitotic delay and chromosome aberrations seen after releasing cells from the plateau phase were investigated. Neither increasing nor decreasing the pHe of the spent medium had an effect on radiation-induced mitotic delay. Rejoining of DSBs was significantly inhibited by holding at pHe 6.0 but not affected by holding at pHe 7.6. At 2 h after irradiation about 51% of unrejoined breaks remained at pHe 6.0, compared to about 15% at pHe 6.7 or 7.6. However, holding at pHe 7.6 appeared to cause a marginal change in the kinetics of rejoining of DSBs. Repair of lesions leading to dicentric and acentric chromosome aberrations did not occur when cells were held at pHe 6.0, since less than 10% of these aberrations disappeared from cells held for 24 h before subculture. In contrast, holding plateau-phase cells at pHe 7.6 vs 6.7 caused a small but significant reduction in the disappearance of dicentrics but had no effect on the rate or extent of the disappearance of acentrics. These data have led us to hypothesize that inhibition of PLD repair by holding at pHe 6.0 is related both to inhibition of pH-dependent DNA repair enzymes and to induction of changes in DNA which lead to misrepair when the cells are released from plateau phase. Inhibition of PLD repair by holding at pHe 7.6, on the other hand, is related primarily to changes in DNA structure which promote misrepair.
The radiomimetic drug bleomycin induced chromosomal aberrations (CA) and micronuclei (MN) were studied in peripheral blood lymphocytes (PBL), as reference to normal cells and Glioma (BMG -1) as reference to tumor cells, with and without exposure to 2-deoxy D-glucose (2-DG, an analogue of glucose). Treatment with bleomycin increased both CA and MN frequency in a dose dependent manner in both cell types. The frequencies of CA are 2 fold higher than MN for a given concentration of bleomycin. Exposure to bleomycin predominantly induced exchange type chromosome aberrations. While in the presence of 2-DG the aberrations induced by bleomycin reduced significantly in PBL, the same was increased significantly in BMG cells (P<0.001) showing a protective effect and sensitizing effect on normal and tumor cells respectively. The dose modulatory factor (protection) for different concentration of bleomycin exposure varied between 0.38 and 0.72 for CA and 0.1 and 0.84 for MN in PBL. In the case of BMG-1 cells, the modulatory factor (sensitization) varied between 1.42 and 2.59 for CA, 1.25 and 1.66 for MN at different concentration of bleomycin exposure. The modulatory effect of 2-DG was also evidenced from the coefficients obtained for the dose-response curves of the aberrations studied. The paper discusses the types of aberrations induced by bleomycin and the mechanism involved for differential modifications of cytogenetic damage by 2-DG in normal (PBL) and tumor (Glioma) cells.
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.
The effect of 2-deoxy-D-glucose (2-DG), an antimetabolite of glucose was studied in peripheral blood lymphocytes (PBL) exposed to radiomimetic drug bleomycin and an alkylating agent mitomycin-C. The PBL were exposed to 2-DG (5 mM), 30 minutes pretreatment and with Bleomycin (10 to 80 µg/ml) and Mitomycin-C (2 to12 µg/ml) for three hours. The drug as well as 2-DG was removed by washing the cells with HBSS buffer. Then the cells were cultured for 48 hours to study chromosomal aberrations (CA), Translocations (TL) and 72 hours for micronuclei (MN) and Sister Chromatid Exchanges (SCE). Exposures of PBL to Bleomycin and Mitomycin-C showed, a concentration dependent increase in the aberration frequencies, both in the presence and absence of 2-DG. While, the regression analysis showed, that the presence of 2-DG reduced bleomycin induced TL, CA frequencies and Mitomycin-C induced CA and MN frequencies significantly (P<0.001) when compared to PBL treated with the drugs alone, Bleomycin induced MN frequencies and Mitomycin-C induced SCE's reduction were not significant. The difference could be attributed to the mechanism of the action of drugs on the cells. Furthermore the alteration in the cell cycle kinetics, suggest that the presence of 2-DG during drug exposure, alter the cellular environment and delay the cell proliferation and provide sufficient time to repair the damages, could resulted in the reduced aberration frequencies.
To determine the genetic diversity of the human leucocyte antigen (HLA)-A*19 group of alleles in the south Indian Tamil population, we studied 100 random healthy unrelated individuals. The frequency of HLA-A*19 was 37% with A*33 (45.9%), A*32 (29.7%), A*31 (16.2%), A*30 (5.4%), A*29 (2.7%) and A*74 (0%). The frequency distribution of the HLA-A*19 alleles was distinct and revealed marked similarities and variations with other populations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.