We propose to investigate the role of polyamine toxins as potential agents for the treatment of hormone refractory prostatic tumors. This proposal centers on the characterization of aziridinylputrescine which we have shown to be cytotoxic to hormone resistant prostatic cancer cells. We will radiolabel the aziridinyl putrescine to determine whether we are able to enhance its uptake to the same degree that we can enhance putrescines uptake in vivo, i.e. from 4:1 to 100:1. This selective enhancement suggests that we are able to target diamines to the prostate and prostatic tumors. We have observed that modification of one nitrogen, but not both nitrogens allows the amines utilization of the prostatic polyamine transporter. We will therefore synthesize and examine the toxicity of N- 1,N-1 dichloroethylputrescine towards prostatic tumors as well. As these are polyamine toxins and as intracellular modulation of polyamines is associated with altered cell growth, we will examine how these agents effect critical polyamine synthetic enzymes (ODC,SAMDC,SAT), their transcription (Northern analysis of mRNA), polyamine transport activity, polyamine modulated growth functions and cell death associated functions such as TRPM-2. We will evaluate means to enhance their toxic activities in vitro and in vivo against models of rodent and human androgen dependent, sensitive or insensitive tumor model systems. Prostatic cancer is the leading cause of cancer in the adult male. It is the second leading cause of death from cancer in the adult male. There is no treatment available for hormone refractory prostatic cancer. Our long range is to develop new methods to treat hormone resistant prostatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039203-06A1
Application #
3177972
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1984-04-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Pinto, J T; Suffoletto, B P; Berzin, T M et al. (1996) Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. Clin Cancer Res 2:1445-51
Vassallo, P; Matei, C; Heston, W D et al. (1994) AMI-227-enhanced MR lymphography: usefulness for differentiating reactive from tumor-bearing lymph nodes. Radiology 193:501-6
Powell, C T; Fair, W R; Heston, W D (1994) Differential expression of protein kinase C isozyme messenger RNAs in dunning R-3327 rat prostatic tumors. Cell Growth Differ 5:143-9
Manchester, K M; Heston, W D; Donner, D B (1993) Tumour necrosis factor-induced cytotoxicity is accompanied by intracellular mitogenic signals in ME-180 human cervical carcinoma cells. Biochem J 290 ( Pt 1):185-90
Heston, W D (1991) Prostatic polyamines and polyamine targeting as a new approach to therapy of prostatic cancer. Cancer Surv 11:217-38
Scher, H I; Curley, T; Geller, N et al. (1990) Trimetrexate in prostatic cancer: preliminary observations on the use of prostate-specific antigen and acid phosphatase as a marker in measurable hormone-refractory disease. J Clin Oncol 8:1830-8
Heston, W D; Charles, M (1988) Calmodulin antagonist inhibition of polyamine transport in prostatic cancer cells in vitro. Biochem Pharmacol 37:2511-4
Scher, H I; Curley, T; Geller, N et al. (1987) Gallium nitrate in prostatic cancer: evaluation of antitumor activity and effects on bone turnover. Cancer Treat Rep 71:887-93
Heston, W D; Yang, C R; Pliner, L et al. (1987) Cytotoxic activity of a polyamine analogue, monoaziridinylputrescine, against the PC-3 human prostatic carcinoma cell line. Cancer Res 47:3627-31

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