Mechanisms of SEPA 0009-Induced Tumorigenesis in v-ras Ha Transgenic Tg.AC Mice

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-ras Ha 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.

[1]  J. Bucher,et al.  Oral and dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cutaneous papillomas and squamous cell carcinomas in female hemizygous Tg.AC transgenic mice. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  John E. Murphy,et al.  IL-1α, Innate Immunity, and Skin Carcinogenesis: The Effect of Constitutive Expression of IL-1α in Epidermis on Chemical Carcinogenesis1 , 2003, The Journal of Immunology.

[3]  J. Haseman,et al.  The role of transgenic mouse models in carcinogen identification. , 2002, Environmental health perspectives.

[4]  John E. Murphy,et al.  IL-1 alpha, innate immunity, and skin carcinogenesis: the effect of constitutive expression of IL-1 alpha in epidermis on chemical carcinogenesis. , 2003, Journal of immunology.

[5]  Peter Smith,et al.  Application of Genetically Altered Models as Replacement for the Lifetime Mouse Bioassay in Pharmaceutical Development , 2002, Toxicologic pathology.

[6]  K. Thompson,et al.  Evaluation of the Tg.AC Transgenic Mouse Assay for Testing the Human Carcinogenic Potential of Pharmaceuticals—Practical Pointers, Mechanistic Clues, and New Questions , 2002, International journal of toxicology.

[7]  R. Tennant,et al.  Age-dependent skin tumorigenesis and transgene expression in the Tg.AC (v-Ha-ras) transgenic mouse. , 2001, Carcinogenesis.

[8]  R. Tennant,et al.  Radial transformation-associated recombination cloning from the mouse genome: isolation of Tg.AC transgene with flanking DNAs. , 2000, Genomics.

[9]  R. Tennant.  What is a tumor promoter? , 1999, Environmental health perspectives.

[10]  R. Tennant,et al.  Photocarcinogenesis and susceptibility to UV radiation in the v-Ha-ras transgenic Tg.AC mouse. , 1998, The Journal of investigative dermatology.

[11]  J. Haseman,et al.  Spontaneous and Chemically Induced Proliferative Lesions in Tg.AC Transgenic and p53-Heterozygous Mice , 1998, Toxicologic pathology.

[12]  S. Yuspa,et al.  The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. , 1998, Journal of dermatological science.

[13]  R. Tennant,et al.  Kinetics of wound‐induced v‐Ha‐ras transgene expression and papilloma development in transgenic Tg.AC mice , 1997, Molecular carcinogenesis.

[14]  R. Tennant,et al.  Mechanism of skin tumorigenesis by contact sensitizers: the effect of the corticosteroid fluocinolone acetonide on inflammation and tumor induction by 2,4 dinitro-1-fluorobenzene in the skin of the TG.AC (v-Ha-ras) mouse. , 1996, Environmental health perspectives.

[15]  R. Tennant,et al.  Association of tumor development with increased cellular proliferation and transgene overexpression, but not c-Ha-ras mutations, in v-Ha-ras transgenic Tg.AC mice. , 1996, Carcinogenesis.

[16]  S. Yuspa.  The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis--thirty-third G. H. A. Clowes Memorial Award Lecture. , 1994, Cancer research.

[17]  R. Tennant,et al.  Chemically induced skin carcinogenesis in a transgenic mouse line (TG.AC) carrying a v-Ha-ras gene. , 1993, Carcinogenesis.

[18]  E. Proksch.  [Regulation of the epidermal permeability barrier by lipids and hyperproliferation]. , 1992, Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete.

[19]  P. Elias,et al.  Barrier function regulates epidermal DNA synthesis. , 1991, The Journal of clinical investigation.

[20]  R. Cardiff,et al.  v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Balmain,et al.  Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Balmain,et al.  Oncogene activation in chemical carcinogenesis. , 1988, Advances in cancer research.

[23]  J. Sicé.  Tumor-promoting activity of n-alkanes and 1-alkanols , 1966 .

[24]  P. Holsti.  Tumor promoting effects of some long chain fatty acids in experimental skin carcinogenesis in the mouse. , 2009, Acta pathologica et microbiologica Scandinavica.