Abstract

The objective of this proposal is to determine the inhibitory effect of the combined treatments with 13-cis-retinoic acid and Alpha-difluoromethylornithine (DFMO) on 12-0-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor promotion. The application of either 13-cis-retinoic acid or DFMO in conjunction with promotion treatments of TPA to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated skin inhibits skin tumor promotion by different mechanisms. 13-cis-Retinoic acid inhibits TPA-caused increased amount of ornithine decarboxylase (ODC) protein while DFMO is an enzyme-activated irreversible inhibitor (suicide inhibitor) of ODC; both inhibits TPA-induced accumulation of putrescin. Thus, we hypothesize that the combination of 13-cis-retinoic acid and DFMO may show enhanced inhibition of skin tumor promotion at dosage levels below the threshold for undesirable side effects of each when used singly. Specifically, we propose: 1. To delineate the optimal dose combination of 13-cis-retinoic acid and DFMO as given in the diet (13-cis-retinoic acid) and in the drinking water (DFMO) on both TPA-induced skin papillomas and carcinomas; and 2. To evaluate the toxic effects of 13-cis-retinoic acid and DFMO by determining effects on growth rate (body weight) and by a complete necropsy and histopathologic evaluation at the end of the experiment. CD-1 mouse skin tumors will be induced by the initiation (DMBA)-promotion (TPA)-protocol. Doses of 13-cis-retinoic acid and DFMO to be used in the tumor induction experiment will be determined from their inhibitory effect on TPA-caused accumulation of putrescine as determined by high-performance reversed-phase liquid chromatographic system. Every dead and killed mouse will receive a complete postmortem examination to observe the grossly detectable changes in the organs. Tissue samples will be fixed and stained for light microscopic examination of histopathological changes. Since 13-cis-retinoic acid is available for human use and the clinical use of DFMO is under investigation, the information obtained on the effects of combined treatments with 13-cis-retinoic acid and DFMO on tumor formation may be important for the use of these compounds for the prevention or the treatment of human cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036323-02
Application #
3173873
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1984-07-01
Project End
1986-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715