Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice.

Jill Fuhrman, Laura Shafer, Susan Repertinger, Tom Chan, Laura A. Hansen

Research output: Contribution to journalArticle

Abstract

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-rasHa transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.

Original languageEnglish
Pages (from-to)623-630
Number of pages8
JournalToxicologic Pathology
Volume33
Issue number6
StatePublished - 2005

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Carcinogenesis
Skin
Papilloma
Keratin-6
Body Weight
2-n-nonyl-1,3-dioxolane
Tumor Suppressor Genes
Transgenes
Oncogenes
Carcinogens
Hyperplasia
Tumors
Genes
Apoptosis
Molecules
Wounds and Injuries
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Health, Toxicology and Mutagenesis
  • Pathology and Forensic Medicine
  • Toxicology

Cite this

Fuhrman, J., Shafer, L., Repertinger, S., Chan, T., & Hansen, L. A. (2005). Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice. Toxicologic Pathology, 33(6), 623-630.

Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice. / Fuhrman, Jill; Shafer, Laura; Repertinger, Susan; Chan, Tom; Hansen, Laura A.

In: Toxicologic Pathology, Vol. 33, No. 6, 2005, p. 623-630.

Research output: Contribution to journalArticle

Fuhrman, J, Shafer, L, Repertinger, S, Chan, T & Hansen, LA 2005, 'Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice.', Toxicologic Pathology, vol. 33, no. 6, pp. 623-630.
Fuhrman, Jill ; Shafer, Laura ; Repertinger, Susan ; Chan, Tom ; Hansen, Laura A. / Mechanisms of SEPA 0009-induced tumorigenesis in v-rasHa transgenic Tg.AC mice. In: Toxicologic Pathology. 2005 ; Vol. 33, No. 6. pp. 623-630.
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