Relative to TPA promoted controls, intraperitoneal administration of recombinant DNA-derived murine gamma interferon (rMuIFN-gamma) to DMBA initiated mice within 24h of TPA promotion, elevated papilloma multiplicities and accelerated the progression of papillomas into carcinomas. Since treatment of initiated mice with only rMuIFN-gamma did not promote the development of any skin tumors, it functioned as a copromoter with TPA. A model for IFN-gamma action consistent with our data is that copromotion and accelerated tumor progression are a consequence of IFN-gamma dependent macrophage activation which results in amplification of a TPA triggered respiratory burst in cutaneous macrophages. To test this hypothesis and further characterize the phenomenon of IFN-gamma dependent copromotion we will determine whether conditions facilitating copromotion actually amplify the respiratory burst of TPA-stimulated macrophages and whether measurements or vascular permeability and ornithine decarboxylase can be used as short term diagnostics of copromotion the murine skin multistage carcinogenesis model will be used to determine: a) whether macrophage activation is required for copromotion; and b) if IFN-gamma can function as a copromoter with non-phorbol ester tumor promoting agents; and c) if IFN-gamma can facilitate the progression of papillomas into carcinomas in the absence of TPA. Lastly, papilloma multiplicities in TPA promoted mice and mice receiving TPA plus macrophages isolated from mice activated in vivo with IFN-gamma will be compared to directly assess the role of macrophages in mediating copromotion. These studies have human health relevance due to the therapeutic and prophylactic uses of IFNs. Furthermore, they are novel because they clearly demonstrate the concept of copromotion and suggest that chemically induced skin cancer can be effected through systemic modulation of components of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049935-02
Application #
3194291
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1989-09-01
Project End
1993-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
McCabe Jr, M J; Singh, K P; Reiners Jr, J J (2001) Low level lead exposure in vitro stimulates the proliferation and expansion of alloantigen-reactive CD4(high) T cells. Toxicol Appl Pharmacol 177:219-31
McCabe Jr, M J; Singh, K P; Reiners Jr, J J (1999) Lead intoxication impairs the generation of a delayed type hypersensitivity response. Toxicology 139:255-64
Reiners Jr, J J; Singh, K P; Yoon, H L et al. (1997) Transplantation analyses of the immunogenicity of epidermal tumors generated in murine skin two-stage carcinogenesis protocols. Mol Carcinog 20:48-57
Reiners Jr, J J; Singh, K P (1997) Susceptibility of 129/SvEv mice in two-stage carcinogenesis protocols to 12-O-tetradecanoylphorbol-13-acetate promotion. Carcinogenesis 18:593-7
Yoon, H L; Singh, K P; Ratner, S et al. (1996) Phorbol ester effects on splenic lymphocyte composition and cytotoxic T cell activities of SSIN mice: a strain deficient in CD8+ T cells. Carcinogenesis 17:2617-24
Singh, K P; Yoon, H L; Ratner, S et al. (1996) Modulation of the development of humoral immunity by topically applied acetone, ethanol, and 12-O-tetradecanoylphorbol-13-acetate. Fundam Appl Toxicol 33:129-39
Kodari, E; Pavone, A; Reiners Jr, J J (1993) Differential modulation of contact hypersensitivity and delayed hypersensitivity reactions by topical application of 12-O-tetradecanoylphorbol-13-acetate. Immunopharmacol Immunotoxicol 15:639-47
Reiners Jr, J J; Cantu, A; Thai, G et al. (1993) Differential co-promoting activities of alpha, beta and gamma interferons in the murine skin two-stage carcinogenesis model. Carcinogenesis 14:367-72
Reiners Jr, J J; Pavone, A; Maldve, R et al. (1993) 12-O-tetradecanoylphorbol-13-acetate-mediated systemic co-promotion in the murine skin multistage carcinogenesis protocol. Carcinogenesis 14:411-5
Gimenez-Conti, I B; Bianchi, A B; Fischer, S M et al. (1992) Dissociation of sensitivities to tumor promotion and progression in outbred and inbred SENCAR mice. Cancer Res 52:3432-5

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