No consistent pattern of mutations inp53 andras genes in liver tumors of rat treated with the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX)

Komulainen, Hannu; Hakulinen, Pasi; Servomaa, Kristina; Makkonen, Kaisa; Vasara, Ritva; Mäki‐Paakkanen, Jorma; Kosma, Veli‐Matti

doi:10.1002/1098-2280(2000)36:4<292::aid-em5>3.0.co;2-3

Cited by 12 publications

(3 citation statements)

References 51 publications

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“…It is clearly genotoxic in mammalian cells in vitro (Hirose et al, 1999). The MX-induced liver tumors in rats contained, however, only a few point mutations in p53 and ras genes (Komulainen et al, 2000b). Furthermore, MX enhanced malignant foci formation in the two stage-cell transformation assay in C3H 10T1/2 cells and inhibited potently gap junction intercellular communication (at nanomolar concentrations) in vitro (Hakulinen et al, 2004).…”

Section: Chlorinated Furanonesmentioning

confidence: 99%

Experimental cancer studies of chlorinated by-products

Komulainen¹

2004

Toxicology

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107

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Section: Chlorinated Furanonesmentioning

confidence: 99%

Experimental cancer studies of chlorinated by-products

Komulainen¹

2004

Toxicology

Self Cite

107

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“…Relatively little information is available regarding the role of K-ras codon 12 mutations in rat liver tumor development. A few studies have reported data on K-ras codon 12 mutations in rat liver tumors (12)(13)(14), with K-ras codon 12 mutations being found only in liver tumors induced by treatment with high doses of nitroglycerin (15). However, the most sensitive mutation detection method applied to the detection of K-ras liver mutation is single-strand conformation polymorphism (SSCP) analysis.…”

Section: Introductionmentioning

confidence: 99%

ACB-PCR measurement of K-ras codon 12 mutant fractions in livers of Big Blue(R) rats treated with N-hydroxy-2-acetylaminofluorene

et al. 2006

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K-ras codon 12 GGT-->GAT and GGT-->GTT mutations are the most frequently observed K-ras point mutations in human and rodent tumors and therefore are implicated in carcinogenesis for many tissues. Measurement of these mutations in rat models and human tissue could facilitate a more logical extrapolation of rodent tumorigenesis data to human disease. We have developed allele-specific competitive blocker PCR (ACB-PCR) assays for rat K-ras codon 12 GGT-->GTT and GGT-->GAT mutations that parallel the already published assays for human K-ras codon 12 mutations. Liver K-ras codon 12 mutant allele fractions were measured in vehicle-treated and N-hydroxy-2-acetylaminofluorene (N-OH-AAF)-treated Big Blue rats. The average K-ras codon 12 GGT-->GTT mutant fraction (MF) for four control rats was 50 x 10(-6) (95% CI: 27 x 10(-6), 95 x 10(-6)) and for four treated rats was 165 x 10(-6) (95% CI: 87 x 10(-6), 312 x 10(-6)), indicating a 3.3-fold increase with treatment (95% CI: 1.3-8.1). The average MF of K-ras codon 12 GGT-->GAT for control rats was 1320 x 10(-6) (95% CI: 498 x 10(-6), 3500 x 10(-6)) and for treated rats was 8450 x 10(-6) (95% CI: 3180 x 10(-6), 22 400 x 10(-6)), indicating a 6.4-fold increase with treatment (95% CI: 1.6-25.4). These transgenic rats were part of a study that included analysis of liver lacI mutations. Although data from lacI determinations show that this compound induces mostly G-->T mutations, using the ACB-PCR method both K-ras codon 12 GGT-->GTT and GGT-->GAT MFs were significantly increased in treated rats versus control rats. This data raises the possibility that N-OH-AAF may not only induce mutations by a genotoxic mechanism, but also by amplification of both de novo and pre-existing K-ras mutation.

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“…We have shown that the MX-induced development of the follicular tumors in the thyroid glands of rats was not caused by TSH-mediated hormonal promotion (Komulainen et al 1997(Komulainen et al , 2000a, indicating that other mechanisms were involved. We could not consistently detect point mutations in p53 (exons 4±7), and not at all in Ki-ras, Ha-ras or N-ras (exons 1 and 2) genes in MX-induced rat liver tumors (Komulainen et al 2000b). On the other hand, Nishikawa et al (1999) reported that, after initiation by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and a NaCl diet, MX increased the development of the atypical hyperplasia and adenocarcinomas in the glandular stomach of Wistar rats.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of 3-methylcholanthrene-induced neoplastic transformation by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone in the two-stage transformation assay in C3H 10T1/2 cells

Laaksonen¹,

Mäki‐Paakkanen²,

Komulainen³

2001

Archives of Toxicology

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3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)furanone (MX) is a mutagenic by-product found in chlorinated drinking water. It is a multi-site carcinogen in Wistar rats although the mechanisms of action of the carcinogenesis remain unresolved. We evaluated the ability of MX to promote development of transformation foci in a two-stage cell transformation assay in vitro. C3H 10T1/2 mouse embryonic fibroblasts were exposed to 3-methylcholanthrene (MC, 5 microg/ml) in the initiation phase and to MX (0.5, 1 or 2 microg/ml) or the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA, the positive control, 0.3 microg/ml) during the promotion phase of the assay on dishes. In other experiments, the cells were exposed to MX (0.5, 5 or 10 microg/ml) only in the initiation phase. At the end of the assay (6 weeks from the start of the assay), the transformation foci were counted and scored after fixation and staining of the cells. MC increased the total number of transformation foci per dish and the number of malignant type III foci, and TPA further promoted this phenomenon. When MX was added during the promotion phase in the MC-initiated cells, it promoted the development of the transformation foci in a dose-dependent manner. MX alone (added as an initiator) also slightly increased the development of the foci, including the malignant forms (type II and III), but the effect was not dose-dependent. In contrast to MC-induced foci, TPA did not promote the development of MX-initiated foci, it even decreased their number. The results suggest that MX may also have potential to promote tumor development.

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No consistent pattern of mutations inp53 andras genes in liver tumors of rat treated with the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX)

Cited by 12 publications

References 51 publications

Experimental cancer studies of chlorinated by-products

Experimental cancer studies of chlorinated by-products

ACB-PCR measurement of K-ras codon 12 mutant fractions in livers of Big Blue(R) rats treated with N-hydroxy-2-acetylaminofluorene

Enhancement of 3-methylcholanthrene-induced neoplastic transformation by 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5 H )-furanone in the two-stage transformation assay in C3H 10T1/2 cells

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