1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.

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Hdl Handle:
http://hdl.handle.net/10541/85587
Title:
1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.
Authors:
Colussi, Claudia; Fiumicino, Silvia; Giuliani, Alessandro; Rosini, Sandra; Musiani, Piero; Macrí, Caterina; Potten, Christopher S; Crescenzi, Marco; Bignami, Margherita
Abstract:
BACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent. METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided. RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2. CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.
Affiliation:
Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Rome, Italy.
Citation:
1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice. 2001, 93 (20):1534-40 J. Natl. Cancer Inst.
Journal:
Journal of the National Cancer Institute
Issue Date:
17-Oct-2001
URI:
http://hdl.handle.net/10541/85587
PubMed ID:
11604476
Type:
Article
Language:
en
ISSN:
0027-8874
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorColussi, Claudiaen
dc.contributor.authorFiumicino, Silviaen
dc.contributor.authorGiuliani, Alessandroen
dc.contributor.authorRosini, Sandraen
dc.contributor.authorMusiani, Pieroen
dc.contributor.authorMacrí, Caterinaen
dc.contributor.authorPotten, Christopher Sen
dc.contributor.authorCrescenzi, Marcoen
dc.contributor.authorBignami, Margheritaen
dc.date.accessioned2009-11-06T16:27:32Z-
dc.date.available2009-11-06T16:27:32Z-
dc.date.issued2001-10-17-
dc.identifier.citation1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice. 2001, 93 (20):1534-40 J. Natl. Cancer Inst.en
dc.identifier.issn0027-8874-
dc.identifier.pmid11604476-
dc.identifier.urihttp://hdl.handle.net/10541/85587-
dc.description.abstractBACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent. METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided. RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2. CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.en
dc.language.isoenen
dc.subjectColonic Canceren
dc.subjectKidney Canceren
dc.subjectRenal Canceren
dc.subjectHaemangiosarcomaen
dc.subject.mesh1,2-Dimethylhydrazine-
dc.subject.meshAdenocarcinoma-
dc.subject.meshAlkylating Agents-
dc.subject.meshAnimals-
dc.subject.meshApoptosis-
dc.subject.meshBase Pair Mismatch-
dc.subject.meshCarcinogens-
dc.subject.meshCell Division-
dc.subject.meshColon-
dc.subject.meshColonic Neoplasms-
dc.subject.meshDNA Repair-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshDrug Resistance-
dc.subject.meshGenotype-
dc.subject.meshHair Diseases-
dc.subject.meshHair Follicle-
dc.subject.meshHemangiosarcoma-
dc.subject.meshIntestinal Mucosa-
dc.subject.meshIntestine, Small-
dc.subject.meshKidney Neoplasms-
dc.subject.meshLymphoma, Non-Hodgkin-
dc.subject.meshMethylation-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMutS Homolog 2 Protein-
dc.subject.meshNeoplasms, Basal Cell-
dc.subject.meshProto-Oncogene Proteins-
dc.title1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.en
dc.typeArticleen
dc.contributor.departmentLaboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Rome, Italy.en
dc.identifier.journalJournal of the National Cancer Instituteen

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