Our long-range goal is to develop effective therapies for prostatic cancer. We have shown that aziridinyl putrescine (AZP) is toxic to prostatic cells. We propose to synthesize 3H-aziridinyl putrescine in order to determine its uptake, metabolism, and covalent binding to DNA, RNA and protein. We have shown that polyamine depletion by inhibitors of polyamine synthesis such as alpha-difluoromethylornithine reduces intracellular content of polyamines in the prostate and prostatic cell lines in vivo and in vitro. This is accompanied by an enhanced uptake of extracellular amines such as putrescine and AZP. The resultant increased uptake of AZP into the polyamine-depleted cell increases AZP's cytotoxic activity. Other manipulations have been shown to increase or decrease cellular uptake of polyamines and putrescine. Using cell growth assays, we will similarly determine whether these manipulations will increase or decrease the toxicity of AZP. AZP is an aziridine and potential alkylating agent. We will also examine the activity of biochemical response modifiers and other cytotoxic agents for their ability to enhance the toxicity of AZP. We will determine the uptake of AZP into R3327 slow-growing, well-differentiated Copenhagen rat prostatic tumor variants and human tumor xenographs in vitro. We will investigate those tumors with high AZP uptake to determine whether they will demonstrate a cytotoxic response to AZP in vivo. We will synthesize new cytotoxic derivatives of putrescine and determine whether these agents are similarly toxic to prostate cells. Prostatic cancer is the second major cause of cancer deaths in adult males in the United States. No effective forms of chemotherapy are available to treat this disease. Because of the high uptake of putrescine into prostatic tissue, it may be that cytotoxic putrescine derivatives offer a new avenue to approach the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039203-03A2
Application #
3177970
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-04-01
Project End
1990-07-31
Budget Start
1987-08-01
Budget End
1988-07-31
Support Year
3
Fiscal Year
1987
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
Pinto, J T; Qiao, C; Xing, J et al. (1997) Effects of garlic thioallyl derivatives on growth, glutathione concentration, and polyamine formation of human prostate carcinoma cells in culture. Am J Clin Nutr 66:398-405
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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