Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model

Gary D. Steinberg, Charles B. Brendler, Tomohiko Ichikawa, John Tod Isaacs, John T. Isaacs

Research output: Contribution to journalArticle

Abstract

Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67% of the lesions are histological Grade II or III. By 20 wk, 83% have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.

Original languageEnglish (US)
Pages (from-to)6668-6674
Number of pages7
JournalCancer Research
Volume50
Issue number20
StatePublished - Oct 15 1990

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Methylnitrosourea
Urinary Bladder Neoplasms
Proto-Oncogene Proteins p21(ras)
Urinary Bladder
Transitional Cell Carcinoma
Neoplasms
Codon
Karyotype
Papillary Carcinoma
Carcinoma in Situ
Inbred F344 Rats
Diploidy
Cytogenetics
Carcinogens
Glycine
Hyperplasia
Glutamic Acid
Lymphoma
Histology
Leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Steinberg, G. D., Brendler, C. B., Ichikawa, T., Isaacs, J. T., & Isaacs, J. T. (1990). Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. Cancer Research, 50(20), 6668-6674.

Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. / Steinberg, Gary D.; Brendler, Charles B.; Ichikawa, Tomohiko; Isaacs, John Tod; Isaacs, John T.

In: Cancer Research, Vol. 50, No. 20, 15.10.1990, p. 6668-6674.

Research output: Contribution to journalArticle

Steinberg, GD, Brendler, CB, Ichikawa, T, Isaacs, JT & Isaacs, JT 1990, 'Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model', Cancer Research, vol. 50, no. 20, pp. 6668-6674.
Steinberg GD, Brendler CB, Ichikawa T, Isaacs JT, Isaacs JT. Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. Cancer Research. 1990 Oct 15;50(20):6668-6674.
Steinberg, Gary D. ; Brendler, Charles B. ; Ichikawa, Tomohiko ; Isaacs, John Tod ; Isaacs, John T. / Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model. In: Cancer Research. 1990 ; Vol. 50, No. 20. pp. 6668-6674.
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abstract = "Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67{\%} of the lesions are histological Grade II or III. By 20 wk, 83{\%} have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.",
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