The mismatch repair complex hMutSα recognizes 5-fluorouracil-modified DNA: Implications for chemosensitivity and resistance

Tajima, Akihiro; Heß, Martin; Cabrera, Betty L.; Kolodner, Richard D.; Carethers, John M.

doi:10.1053/j.gastro.2004.10.001

Cited by 112 publications

(83 citation statements)

References 43 publications

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“…However, others found a significant survival benefit in MSI þ cases who received adjuvant 5-FU-based chemotherapy (Elsaleh et al, 2001). These conflicting results may be explained by preclinical studies demonstrating that p53, BAX, Bcl-2 and BAT26 in colon cancer O Nehls et al MSI þ tumours were less responsive to 5-FU as compared to MSIÀ lesions (Carethers et al, 1999), which has been attributed to the observation that mismatch repair proteins may be essential to incorporate 5-FU into tumour DNA (Tajima et al, 2004), whereas others found that MSI þ tumours may harbour an intrinsic favourable prognosis (Popat et al, 2005). Notably, bivariate subgroup analysis showed a nonsignificant trend for survival benefit for patients with the BSI high/MSI þ phenotype as compared to those with the BSI high/MSIÀ phenotype.…”

Section: Discussionmentioning

confidence: 99%

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

et al. 2007

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We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify highfrequency microsatellite instability (MSI þ ) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/ levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI þ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P ¼ 0.01 or P ¼ 0.03, respectively); MSI was correlated with right-sided tumours (Po0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P ¼ 0.0005, P ¼ 0.001, P ¼ 0.005 and P ¼ 0.01, respectively) and poorer overall survival (OS) (P ¼ 0.002, P ¼ 0.0001, P ¼ 0.003 and P ¼ 0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P ¼ 0.003 and P ¼ 0.001, respectively). In both univariate and multivariate analysis, the p53À/BAX high in comparison with the p53 þ /BAX high subset conferred a significantly improved DFS (P ¼ 0.03 and P ¼ 0.03, respectively) as well as a marginally improved OS (P ¼ 0.07 and P ¼ 0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.

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Section: Discussionmentioning

confidence: 99%

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

et al. 2007

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“…Numerous studies have made direct comparisons between MSI CRC with and without 5-FU chemotherapy (Ribic et al, 2003;Tajima et al, 2004) (Benatti et al, 2005;Jover et al, 2006). Many early studies outlined an increased sensitivity of MSI patients to 5-FU treatment (Elsaleh et al, 2000;Hemminki et al, 2000;Jover et al, 2006;Jover et al, 2009).…”

Section: Predictive Significance Of Msi For 5-fu-based Chemotherapy (Seementioning

confidence: 99%

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Ryan

Sheahan

Creavin

et al. 2017

Critical Reviews in Oncology/Hematology

118

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“…54,55 In vitro, 5-FU-containing DNA oligonucleotides are bound directly by purified hMSH2/hMSH6 and released by ATP. 56 While 5-FU inhibits thymidylate synthase and is primarily incorporated into RNA, the cytotoxic effect appears to stem from 5-FU incorporation into DNA. 57 hMSH2 and hMLH1 are both required for efficient killing by 5-FU.…”

Section: Regulation Of Mmrmentioning

confidence: 99%

Structure and function of the components of the human DNA mismatch repair system

Jascur

Boland

2006

Intl Journal of Cancer

103

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DNA mismatch repair (MMR) is one of the several enzyme systems involved in DNA homeostasis. DNA MMR is involved in the repair of specific types of errors that occur during new DNA synthesis; loss of this system leads to an accelerated accumulation of potential mutations, and predisposes to certain types of cancers. Germline mutations in some of the DNA MMR genes cause the hereditary cancer predisposition, Lynch syndrome. This review addresses advances in the biochemistry of DNA MMR and its relationship to carcinogenesis. ' 2006 Wiley-Liss, Inc.Key words: DNA mismatch repair; microsatellite instability; lynch syndrome; HNPCC; colorectal cancer; hMSH2; hMLH1; hMSH6; hPMS2; exonuclease IThe DNA mismatch repair (MMR) system was at one time in the exclusive domain of the microbial biochemist, but has been thrust into the mainstream of the cancer biologist because of its importance in carcinogenesis. Approximately 15% of colorectal cancers develop through mechanisms whereby this form of DNA maintenance is lost, leading to 100-to 1,000-fold increases in error rates during replication. This review of recent progress in DNA MMR research is intended for the tumor biologist who is interested in structural and functional details of this system. There have been several reviews of the clinical aspects of DNA MMR that emphasize the diagnostic uses of testing for microsatellite instability and the use of immunohistochemistry of the DNA MMR proteins in colorectal cancer. [1][2][3][4][5][6][7] This review will serve to complement those reviews, and will highlight some of the biochemical issues that underlie DNA MMR. Components of the DNA MMR systemThe DNA MMR system corrects DNA base pairing errors in newly replicated DNA. The primary DNA polymerase in eukaryotic S phase DNA replication, polymerase d, has 3 0 > 5 0 proofreading activity that corrects 99% of replication errors. Nevertheless, mispaired nucleotides are occasionally left behind, as are small insertion/deletion mutations that are prone to occur at repetitive sequences. Microsatellites are multiple tandem repeats in which the repetitive element consists of a short number of nucleotides (perhaps 6 or fewer, and for functional studies, usually 1-4), and these are particularly prone to slippage and inefficient proofreading by DNA polymerase. The MMR system is critical to correct these problems, and if inactivated, the resulting shortening of microsatellites is a telltale sign of the ensuing ''microsatellite instability'' (MSI) phenotype. MSI testing is most often performed on mononucleotide or dinucleotide repeats.A casual description of the MMR system would state that the MMR system is chiefly a sensory system that scans DNA, and when a nucleotide mispair is detected, removes the error and summons DNA polymerase to repeat the synthesis, and this time corrects the error. This works because even in repetitive sequences, the error rate of DNA polymerase is low, and so simply having a second chance usually fixes the problem.More formally, the MMR system is an excision/resynt...

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The mismatch repair complex hMutSα recognizes 5-fluorouracil-modified DNA: Implications for chemosensitivity and resistance

Cited by 112 publications

References 43 publications

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

Structure and function of the components of the human DNA mismatch repair system

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