Relationship between dose, time, and tumor yield in mouse dimethylhydrazine-induced colon tumorigenesis

Long, Florence C.; Maskens, Alain P.

doi:10.1016/0304-3835(79)90018-1

Cited by 18 publications

(13 citation statements)

References 16 publications

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“…DMH was used to induce colonic tumours in wild‐type, heterozygous K‐ ras tm Δ4 A /+ and homozygous K‐ ras tm Δ4 A / tm Δ4 A mice. Although activating K‐ ras mutations have sometimes been detected in DMH‐induced bowel tumours in the rat model 25, they were not detected in colonic adenomas in mouse models investigated here or elsewhere 26–28. K‐ ras tm Δ4 A / tm Δ4 A mice exhibit normal life expectancy and an overall similar spontaneous tumour incidence to that of wild‐type mice 16, indicating that K‐ ras tm Δ4 A / tm Δ4 A mice provide an excellent experimental model to explore the effects of K‐ ras 4A and 4B isoforms on colonic tumourigenesis.…”

Section: Introductionmentioning

confidence: 76%

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

Luo

Hamoudi

et al. 2010

The Journal of Pathology

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K-ras encodes two isoforms, K-ras 4A and 4B, that are jointly affected by K-ras activating mutations, which are prevalent in colorectal cancer (CRC). CRC shows alterations in the expressed K-ras 4A : 4B isoform ratio in favour of K-ras 4B, in tumours both with and without K-ras mutations. The present study evaluated whether K-ras 4A expression can suppress colonic adenoma development in the absence of its oncogenic allele. Mice with homozygous targeted deletions of K-ras exon 4A (K-ras(tmDelta4A/tmDelta4A)) that can express the K-ras 4B isoform only, along with heterozygous K-ras(tmDelta4A/+) and wild-type mice, were given ten weekly 1,2-dimethylhydrazine (DMH) treatments to induce colonic adenomas. There was a significant increase in both the number and the size of colonic adenomas in DMH-treated K-ras(tmDelta4A/tmDelta4A) mice, with reduced survival, compared with heterozygous and wild-type mice. No K-ras mutations were found in any of the 30 tumours tested from the three groups. Lack of expression of K-ras 4A transcripts was confirmed, whereas the relative expression levels of K-ras 4B transcripts were significantly increased in the adenomas of K-ras(tmDelta4A/tmDelta4A) mice compared with K-ras(tmDelta4A/+) and wild-type mice. Immunohistochemical studies showed that adenomas of K-ras(tmDelta4A/tmDelta4A) mice had significantly increased cell proliferation and significantly decreased apoptosis with evidence of activation of MapKinase and Akt pathways, with increased phospho-Erk1/2 and both phospho-Akt-Thr308 and phospho-Akt-Ser473 immunostaining, compared with adenomas from K-ras(tmDelta4A/+) and wild-type mice. In conclusion, following DMH treatment, K-ras exon 4A deletion promoted increased number and size of colonic adenomas showing increased K-ras 4B expression, increased proliferation, decreased apoptosis, and activation of MapKinase and Akt pathways, in the absence of K-ras mutations. Therefore, K-ras 4A expression had a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation, explaining the selective advantage of the altered K-ras 4A : 4B isoform ratio found in human colorectal cancer.

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Section: Introductionmentioning

confidence: 76%

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

Luo

Hamoudi

et al. 2010

The Journal of Pathology

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“…Most authors consider that only one dose of 20 mg per kilogram of weight, injected weekly for 26 weeks, may induce a very high incidence of colorectal adenocarcinomas (18,19,(21)(22)(23)(24). However, even in these models a high incidence of tumors may be found, which rarely reaches 100% (25).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethylhydrazine (DMH)

Coca

Enrech

Moreno

et al. 2005

Rev. esp. enferm. dig.

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Objective: interlukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/-IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat -number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumorfree. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p=0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

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“…Previously validated DMH treatments consisted of 10 weekly injections of 20.0 mg/kg, starting at age 7–8 weeks (cumulative dose = 200.0 mg/kg DMH·2HCl or 145.0 mg/kg DMH) (Deschner et al . ; Luo et al . ).…”

Section: Methodsmentioning

confidence: 99%

Wild‐type K‐ras has a tumour suppressor effect on carcinogen‐induced murine colorectal adenoma formation

Luo

Poulogiannis

et al. 2013

Int J Experimental Path

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K-ras mutations are found in ~40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras(+/+) ) and heterozygous K-ras exon 1 knockout (K-ras(+/-) ) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras(+/-) mice were ~50% decreased compared with K-ras(+/+) mice. One year after DMH treatment, survival of K-ras(+/-) mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras(+/+) mice to 0.87 ± 0.14 in K-ras(+/-) mice (mean ± SEM per mouse, P < 0.01); total tumour volume increased 2.13-fold (P < 0.05). Comparing K-ras(+/+) with K-ras(+/-) murine adenomas, Ki-67-positive proliferating tumour cells significantly increased from 7.77 ± 0.64% to 9.15 ± 0.92% and cleaved caspase-3-positive apoptotic tumour cells decreased from 1.40 ± 0.37% to 0.80 ± 0.22% (mean ± SEM, P < 0.05 for both). No K-ras or B-raf mutations were detected in the adenomas. Immunohistochemical studies showed no significant changes in extracellular signal regulating kinase/mitogen-activated protein kinase (Erk/MapK) or PI3K/Akt pathway activation in the adenomas. In conclusion, the data collectively show that a 50% reduction in K-ras gene dosage and RNA expression promoted experimental colorectal tumourigenesis, consistent with wild-type K-ras having a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.

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Relationship between dose, time, and tumor yield in mouse dimethylhydrazine-induced colon tumorigenesis

Cited by 18 publications

References 16 publications

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethylhydrazine (DMH)

Wild‐type K‐ras has a tumour suppressor effect on carcinogen‐induced murine colorectal adenoma formation

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