Mouse anti-Human XRCC2 monoclonal antibody, clone 3I5

Single nucleotide polymorphisms (SNPs) may modify the risk of cancer. They may be then regarded as potential markers of carcinogenesis. The aim of this study was to analyze the frequency of genotypes and alleles of SNPs in DNA repair genes and to investigate the influence this genetic variation exerts on breast cancer in Polish females. The test group comprised 600 females with breast cancer and 600 healthy controls. Genomic DNA was isolated and the SNPs in DNA repair genes were determined by High-Resolution Melter (HRM) technique. Following polymorphisms were analysed: Arg399Gln (rs25487) of the XRCC1, Gly322Asp (rs4987188) of the hMSH2, Lys751Gln (rs13181) of the XPD, Arg188His (rs3218536) of the XRCC2, P871L (rs799917) of the BRCA1 and N372H (rs144848) of the BRCA2 gene. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. Statistically significant correlations were identified between 4 single nucleotide polymorphisms and the breast cancer risk: rs25487 rs4987188 rs13181 and rs799917. The alleles XRCC1-Gln (OR 5.11; 95% CI 5.68-11.64, p < .0001), hMSH2-Asp (OR 4.66; 95% CI 3.90-5.56, p < .0001), XPD-Gln (OR 2.65; 95% CI 2.24-3.14, p < .0001) and BRCA1-L (OR 1.45; 95% CI 1.24-1.71, p < .0001) genes were strongly correlated with this malignancy. No correlation was found between the studied SNPs and tumor grading nor the lymph node status. Further research on larger groups is warranted to determine the influence of above-mentioned genetic variants on breast cancer risk.

SJG-136, a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer, is a highly efficient interstrand crosslinking agent that reacts with guanine bases in a 5'-GATC-3' sequence in the DNA minor groove. SJG-136 crosslinks form rapidly and persist compared to those produced by conventional crosslinking agents such as nitrogen mustard, melphalan or cisplatin which bind in the DNA major groove. A panel of Chinese hamster ovary (CHO) cells with defined defects in specific DNA repair pathways were exposed to the bi-functional agents SJG-136 and melphalan, and to their mono-functional analogues mmy-SJG and mono-functional melphalan. SJG-136 was > 100 times more cytotoxic than melphalan, and the bi-functional agents were much more cytotoxic than their respective mono-functional analogues. Cellular sensitivity of both SJG-136 and melphalan was dependent on the XPF-ERCC1 heterodimer, and homologous recombination repair factors XRCC2 and XRCC3. The relative level of sensitivity of these repair mutant cell lines to SJG-136 was, however, significantly less than with major groove crosslinking agents. In contrast to melphalan, there was no clear correlation between sensitivity to SJG-136 and crosslink unhooking capacity measured using a modified comet assay. Furthermore, repair of SJG-136 crosslinks did not involve the formation of DNA double-strand breaks. SJG-136 cytotoxicity is likely to result from the poor recognition of DNA damage by repair proteins resulting in the slow repair of both mono-adducts and more importantly crosslinks in the minor groove.