Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that human cancer cells deficient in DNA mismatch repair (MMR) are resistant to the chemotherapeutic methylating agent temozolomide (TMZ) and can be sensitized by the base excision repair (BER) blocking agent methoxyamine (MX) [21]. To further characterize BER-mediated repair responses to methylating agent-induced DNA damage, we have now evaluated the effect of MX on TMZ-induced DNA single strand breaks (SSB) by alkaline elution and DNA double strand breaks (DSB) by pulsed field gel electrophoresis in SW480 (O6-alkylguanine-DNA-alkyltransferase [AGT]+, MMR wild type) and HCT116 (AGT+, MMR deficient) colon cancer cells. SSB were evident in both cell lines after a 2-h exposure to equitoxic doses of temozolomide. MX significantly increased the number of TMZ-induced DNA-SSB in both cell lines. In contrast to SSB, TMZ-induced DNA-DSB were dependent on MMR status and were time-dependent. Levels of 50 kb double stranded DNA fragments in MMR proficient cells were increased after TMZ alone or in combination with O6-benzylguanine or MX, whereas, in MMR deficient HCT116 cells, only TMZ plus MX produced significant levels of DNA-DSB. Levels of AP endonuclease, XRCC1 and polymerase beta were present in both cell lines and were not significantly altered after MX and TMZ. However, cleavage of a 30-mer double strand substrate by SW480 and HCT116 crude cell extracts was inhibited by MX plus TMZ. Thus, MX potentiation of TMZ cytotoxicity may be explained by the persistence of apurinic/apyrimidinic (AP) sites not further processed due to the presence of MX. Furthermore, in MMR-deficient, TMZ-resistant HCT116 colon cancer cells, MX potentiates TMZ cytotoxicity through formation of large DS-DNA fragmentation and subsequent apoptotic signalling.
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PMID:Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells. 1158 61

5-Iodo-2'-deoxyuridine (IdUrd) is a halogenated thymidine analogue recognized as an effective in vitro and in vivo radiosensitizer in human cancers. IdUrd-related cytotoxicity and/or radiosensitization are correlated with the extent of IdUrd-DNA incorporation replacing thymidine. IdUrd cytotoxicity and radiosensitization result, in part, from induction of DNA single-strand breaks (SSB) with subsequent enhanced DNA double-strand breaks leading to cell death. Because base excision repair (BER) is a major DNA repair pathway for SSB induced by chemical agents and ionizing radiation, we initially assessed the role of BER in modulating IdUrd cytotoxicity and radiosensitization using genetically matched Chinese hamster ovary cells, with (AA8 cells) and without (EM9 cells) XRCC1 expression. XRCC1 plays a central role in processing and repairing SSBs and double-strand breaks. We found that EM9 cells were significantly more sensitive than parental AA8 cells to IdUrd alone and to IdUrd + ionizing radiation. The EM9 cells also demonstrate increased DNA damage after IdUrd treatment as evaluated by pulse field gel electrophoresis and single cell gel electrophoresis (Comet Assay). BER-competent EM9 cells, which were stably transfected with a cosmid vector carrying the human XRCC1 gene, showed responses to IdUrd similar to AA8 cells. We also assessed the role of methoxyamine, a small molecule inhibitor of BER, in the response of human colon cancer cells (HCT116) to IdUrd cytotoxicity and radiosensitization. Methoxyamine not only was able to increase IdUrd cytotoxicity but also increased the incorporation of IdUrd into DNA of HCT116 human colon cancer cells leading to greater radiosensitization. Thus, a genetic or biochemical impairment of BER results in increased IdUrd-induced cytotoxicity and radiosensitization in mammalian cells.
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PMID:Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization. 1259 35

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.
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PMID:DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study. 1800 25

Colorectal cancer is the second most frequent cause of death among malignant diseases. The mortality of head and neck cancer in Hungary increased by 265 percent in the last thirty years. Both malignancies belong to the most current public health problems in Hungary. The influence of two allelic polymorphisms of GSTM1 and GSTT1, and that of p53 gene codon 72 on colon cancer was investigated. In case of head and neck cancer the effects of the Arg194Trp and Arg399Gln polymorphisms of XRCC1 gene were analyzed. Intraoperative removed tissue samples were processed and cancer free human samples were used as matched controls. The formalin fixed samples were deparaffinized and digested with proteinase K. Genotyping was performed by PCR amplification, and in case of head and neck cancer a PCR-RFLP method was applied. No significant difference was found between tumor patients and controls in the investigated polymorphisms. A significant difference in survival was found between the GSTM1 and p53 gene variants in Dukes'B stage colorectal patients. The survival difference among the XRCC1 194 alleles by head and neck patients in clinical stage III proved to be also significant. The complex analysis of this type of genetic variants may be the future way of the personal risk assessment and the real chance for personal therapy.
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PMID:[Genetic polymorphism in patients with colorectal and with head and neck cancer]. 1964 19

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer.
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PMID:Assessing tumor mutations to gain insight into base excision repair sequence polymorphisms and smoking in colon cancer. 1995 86

Animal and in vitrostudies support a role for polyunsaturated fatty acids (PUFAs) in colon carcinogenesis; however, the epidemiological evidence is inconclusive. Recently, we investigated their role within the Singapore Chinese Health Study, a population-based cohort of Singapore Chinese men and women. We reported that a high intake of marine n-3 PUFAs was associated with an increased risk of colorectal cancer (CRC). Oxidation of PUFAs incorporated into cell membranes generates lipid hydroperoxides, which can be mutagenic. In this report, we investigated whether single nucleotide polymorphisms (SNPs) in DNA repair genes modified the effect of PUFAs on CRC risk using a nested case-control study within the Singapore Chinese Health Study. We genotyped 1,181 controls and 311 cases (180 colon and 131 rectal cancer) for SNPs in the XRCC1 (Arg194Trp, Arg399Gln), OGG1 (Ser326Cys), PARP (Val762Ala, Lys940Arg), and XPD (Asp312Asn, Lys751Gln) genes. We observed that the PARP Val762Ala SNP modified the association between marine n-3 PUFA and rectal cancer risk, with no evidence of interaction among colon cancer (heterogeneity test p=0.003). Our results suggest a positive association between high intake of marine n-3 PUFA and rectal cancer risk among carriers of at least one PARP codon 762 Ala allele (odds ratio=1.7, 95% confidence interval=1.1-2.7).
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PMID:Polyunsaturated fatty acids, DNA repair single nucleotide polymorphisms and colorectal cancer in the Singapore Chinese Health Study. 2055 12

Single-nucleotide polymorphisms in genes involved in DNA-damage-induced responses are reported frequently to be a risk factor in various cancer types. Here we analysed polymorphisms in 5 genes involved in DNA repair (XPD Asp312Asn and Lys751Gln, XRCC1 Arg399Gln, APE1 Asp148Glu, NBS1 Glu185Gln, and XPA G-4A) and in a gene involved in regulation of the cell-cycle (CCND1 A870G). We compared their frequencies in groups of colon, head and neck, and breast cancer patients, and 2 healthy control groups: (1) matched healthy Polish individuals and (2) a NCBI database control group. Highly significant differences in the distribution of genotypes of the APE1, XRCC1 and CCND1 genes were found between colon cancer patients and healthy individuals. The 148Asp APE1 allele and the 399Gln XRCC1 allele apparently increased the risk of colon cancer (OR = 1.9-2.3 and OR = 1.5-2.1, respectively). Additionally, frequencies of XPD genotypes differed between healthy controls and patients with colon or head and neck cancer. Importantly, no differences in the distribution of these polymorphisms were found between healthy controls and breast cancer patients. The data clearly indicate that the risk of colon cancer is associated with single-nucleotide polymorphism in genes involved in base-excision repair and DNA-damage-induced responses.
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PMID:Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population. 2072 Mar 10

Gene polymorphisms and mutations in various types of cancer may predict clinical response to chemotherapy and related toxicity, since they may affect the metabolism of the drugs commonly used in combination chemotherapy treatments. However, conflicting data have been generated on this subject. To elucidate this issue, this review discusses the clinical applications of several genetic polymorphisms in colorectal cancer patients treated with the most common agents alone or in combination. UDP-glucuronosyltransferase (UGT)1A1 is a conjugating biotransformation enzyme that plays a role in maintaining the levels of endogenous compounds (e.g., bilirubin) and in handling exogenous compounds, including carcinogens. It has been demonstrated that the UGT1A1*28 polymorphism plays a predictive role in patients administered an irinotecan-containing regimen. Polymorphisms in XPD (Lys751Gln), a member of the nucleotide excision repair pathway, negatively affect response to therapy, with oxaliplatin/5FU reducing the survival of the patient. A similar reaction has also been observed in patients with the XRCC1 Arg399Gln polymorphism, while patients with the GSTP1 Ile105Val polymorphism have an improved response to oxaliplatin/5FU therapy. Treatment with biological compounds such as cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be effective only in colon cancer patients with wild-type K-Ras. Fc polymorphisms are associated with progression-free survival in patients treated with cetuximab. Another monoclonal antibody useful in the treatment of colon cancer is bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF); however, in some cases bevacizumab may cause deep vein thrombosis (DVP). In a related vein, our recent unpublished data show that the VEGF C936T polymorphism may increase the risk of DVP in cancer patients. In conclusion, this review indicates that certain polymorphisms increase the effectiveness of certain drugs, while others greatly enhance their toxicity. The study of the genetic 'habitus' therefore appears to be crucial for the development of tailored therapy for cancer patients.
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PMID:Role of genetic polymorphisms and mutations in colorectal cancer therapy (Review). 2146 52

The fluoropyrimidines 5-fluorouracil (5-FU) and FdUrd (5-fluorodeoxyuridine; floxuridine) are the backbone of chemotherapy regimens for colon cancer and other tumors. Despite their widespread use, it remains unclear how these agents kill tumor cells. Here, we have analyzed the checkpoint and DNA repair pathways that affect colon tumor responses to 5-FU and FdUrd. These studies demonstrate that both FdUrd and 5-FU activate the ATR and ATM checkpoint signaling pathways, indicating that they cause genotoxic damage. Notably, however, depletion of ATM or ATR does not sensitize colon cancer cells to 5-FU, whereas these checkpoint pathways promote the survival of cells treated with FdUrd, suggesting that FdUrd exerts cytotoxicity by disrupting DNA replication and/or inducing DNA damage, whereas 5-FU does not. We also found that disabling the base excision (BER) repair pathway by depleting XRCC1 or APE1 sensitized colon cancer cells to FdUrd but not 5-FU. Consistent with a role for the BER pathway, we show that small molecule poly(ADP-ribose) polymerase 1/2 (PARP) inhibitors, AZD2281 and ABT-888, remarkably sensitized both mismatch repair (MMR)-proficient and -deficient colon cancer cell lines to FdUrd but not to 5-FU. Taken together, these studies demonstrate that the roles of genotoxin-induced checkpoint signaling and DNA repair differ significantly for these agents and also suggest a novel approach to colon cancer therapy in which FdUrd is combined with a small molecule PARP inhibitor.
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PMID:Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil. 2219 30

Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients' clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.
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PMID:Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy. 2890 34


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