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Cytotoxic Activity of a Polyamine Analogue, Monoaziridinylputrescine, against the PC-3 Human Prostatic Carcinoma Cell Line

Urologic Oncology Research Laboratory, Urology Service [W. D. W. H., C-R. Y., P. R.], and Solid Tumor Service, Department of Medicine [L. P.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Department of Pharmacology, Washington University, School of Medicine, St. Louis, Missouri 63110 [D. F. C.]

We have previously demonstrated that prostate and prostate-derived rodent tumors can be manipulated into increasing their accumulation of radiolabeled putrescine by -difluoromethylornithine (DFMO)-induced depletion of intracellular putrescine and spermidine. As methods which increase intracellular accumulation of cytotoxic agents often increase the chemotherapeutic effectiveness of the agent, we examined whether an alkylating derivative of putrescine would be cytotoxic to tumor cells. We present here our findings on the cytotoxicity of the aziridinyl derivative of putrescine (AZP) against prostatic cancer cells.

The apparent K_m for putrescine was 2.5 µM with or without DFMO pretreatment and the apparent K_i for AZP was 1 µM with or without DFMO pretreatment. Intracellular polyamine depletion by DFMO pretreatment resulted in a 3.7-fold greater accumulation of AZP compared to non-DFMO-treated cells. The growth inhibitory activity of AZP was increased with prior polyamine depletion by DFMO with the 50% effective dose decreasing from 18 µM to 2.1 µM. Putrescine was able to block the cytotoxic effect of AZP. Putrescine was also able to rescue the AZP-treated PC-3 cells for up to 6 h following a 1-h exposure to AZP.

It appears that aziridinylputrescine behaves like putrescine in that it competes with putrescine for uptake into the cell and, like putrescine, has its uptake into the cell increased by prior polyamine depletion. It differs from putrescine in that it expresses cytotoxic activity and inhibits the growth of the human prostate-derived PC-3 cell line. This cytotoxic activity is also increased by prior polyamine depletion. The cytotoxic behavior of AZP is dependent both on the concentration and duration of exposure. Putrescine can rescue the cells from the effect of AZP. AZP is a potentially useful cytotoxic analogue that utilizes the polyamine transport system for its uptake into the cell.

¹ Supported in part by Grant CA-39203 from the USPHS. To whom requests for reprints should be addressed.

² Supported in part by the Ancell Clinical Studies and Cogan Research Funds.

³ Recipient of NIH Research Career Development Award CA-00829.

Received 7/30/85. Revised 6/10/86. Revised 2/ 2/87. Accepted 4/16/87.