The overall objective of this project is to investigate the differential response of human cancer cells to inhibition of the polyamine pathway. We seek to determine those mechanisms which are responsible for the cytotoxic vs. cytostatic responses exhibited by human tumor cells to polyamine depletion by agents which act at different sites on the polyamine synthetic pathway. Specifically, we will extend our preliminary studies showing that small cell lung carcinoma cells respond cytotoxically to polyamine depletion by 2-difluoromethyl ornithine (DFMO) and only cytostatically to treatment with a new class of polyamine analogs N,N-bis(ethyl)polyamines, whereas, a human large cell undifferentiated lung cancer line responds only cytostatically to DFMO yet responds in a profoundly cytotoxic manner to polyamine depletion by the N,N-bis(ethyl)polyamines. We shall examine, in both cell types, before and after polyamine depletion by DFMO and the analogs, the regulation of ornithine decarboxylase, the first and generally rate limiting step in polyamine biosynthesis at the transcriptional, post- transcriptional, translational, and post-translational levels. Further, we shall examine the effects of polyamine depletion by DFMO and the newly synthesized polyamine analogs on the expression of growth related genes. We will attempt to extend our preliminary results which indicate that polyamine depletion leads to a specific, altered expression of the oncogene, c-myc at the transcriptional level. The above studies should be useful in determining the essential roles which polyamines play in the growth of individual types of human cancer cells. Additionally, the differential sensitivity exhibited to the above agents suggest a potential for selective targeting, a primary goal of any cancer therapy. Thereby, these studies may facilitate the design of new agents for the treatment of human neoplastic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA047492-04
Application #
3458955
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Casero Jr, R A; Pegg, A E (1993) Spermidine/spermine N1-acetyltransferase--the turning point in polyamine metabolism. FASEB J 7:653-61
Celano, P; Berchtold, C M; Kizer, D L et al. (1992) Characterization of an endogenous RNA transcript with homology to the antisense strand of the human c-myc gene. J Biol Chem 267:15092-6
Xiao, L; Celano, P; Mank, A R et al. (1992) Structure of the human spermidine/spermine N1-acetyltransferase gene (exon/intron gene organization and localization to Xp22.1). Biochem Biophys Res Commun 187:1493-502
Casero Jr, R A; Mank, A R; Xiao, L et al. (1992) Steady-state messenger RNA and activity correlates with sensitivity to N1,N12-bis(ethyl)spermine in human cell lines representing the major forms of lung cancer. Cancer Res 52:5359-63
Xiao, L; Celano, P; Mank, A R et al. (1991) Characterization of a full-length cDNA which codes for the human spermidine/spermine N1-acetyltransferase. Biochem Biophys Res Commun 179:407-15
Marks, S C; Mattox, D E; Casero, R A (1991) The effects of DFMO on polyamine metabolism in the inner ear. Hear Res 53:230-6
Casero Jr, R A; Celano, P; Ervin, S J et al. (1990) High specific induction of spermidine/spermine N1-acetyltransferase in a human large cell lung carcinoma. Biochem J 270:615-20
Casero Jr, R A; Ervin, S J; Celano, P et al. (1989) Differential response to treatment with the bis(ethyl)polyamine analogues between human small cell lung carcinoma and undifferentiated large cell lung carcinoma in culture. Cancer Res 49:639-43
Casero Jr, R A; Celano, P; Ervin, S J et al. (1989) Differential induction of spermidine/spermine N1-acetyltransferase in human lung cancer cells by the bis(ethyl)polyamine analogues. Cancer Res 49:3829-33
Celano, P; Baylin, S B; Casero Jr, R A (1989) Polyamines differentially modulate the transcription of growth-associated genes in human colon carcinoma cells. J Biol Chem 264:8922-7