TUMOR-TARGETED APOPTOSIS BY A NOVEL SPERMINE ANALOG, 1,12-DIAZIRIDINYL-4,9-DIAZADODECANE, RESULTS IN THERAPEUTIC EFFICACY AND ENHANCED RADIOSENSITIVITY OF HUMAN PROSTATE-CANCER

Interference with polyamine transport and biosynthesis has emerged as an important anticancer strategy involving polyamine analogues and spe cific inhibitors of key biosynthetic enzymes. Because the prostate gla nd has a high polyamine content, by using the polyamine transporter fo r selective uptake into cancer cells, alkylating polyamines are Likely to be highly effective against prostatic tumors, We have recently syn thesized a novel class of spermine analogues, the lead compound of whi ch has efficacy against human cancer cells (P, S, Callery et at, U. S. patent, 5,612,239, Issued March 17, 1997.), In this study, to investi gate the potential therapeutic efficacy of the lead spermine analogue 1,12-diaziridinyl-4, 9-diazadodecane (BIS), against advanced prostate cancer, rye examined the in vitro effect and ire vivo efficacy of the compound in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. BIS exhibited a dose-dependent cytotoxic effect agai nst prostate cancer cells via induction of apoptosis, Treatment of cel ls with BIS (1 mu M) for 24 h resulted in a significant induction of a poptosis (24%), Exposure of BIS-treated PC-3 prostate cancer cells to gamma-irradiation resulted in a significant increase in the number of cells undergoing apoptosis and a subsequent decrease in the IC50. Furt hermore, BIS treatment led to a significant enhancement of loss of clo nogenic survival in irradiated prostate cancer cells (both PC-3 and DU -145). In vivo efficacy trials demonstrated a significant antitumor ef fect of BIS against both PC-3 and DU-145 tumor xenografts in severe co mbined inmunodeficient mice in a dose-dependent pattern at maximally t olerated doses. Terminal transferase end-labeling analysis indicated t hat EIS-mediated tumor regression in vivo occurs via induction of apop tosis among prostatic tumor cells. These results suggest that the nove l spermine analogue BIS: (a) has a potent antitumor effect against pro static tumors via induction of apoptosis; and (b) increases the radios ensitivity of human prostate cancer cells by decreasing the apoptotic threshold to radiation. This study may have important clinical implica tions for the manipulation of this antitumor activity of the polyamine analogue for the optimization of the therapeutic efficacy of radiatio n in patients with advanced prostate cancer.