Interference with
polyamine transport and biosynthesis has emerged as an important anticancer strategy involving
polyamine analogues and specific inhibitors of key biosynthetic
enzymes. Because the prostate gland has a high
polyamine content, by using the
polyamine transporter for selective uptake into
cancer cells, alkylating
polyamines are likely to be highly effective against prostatic
tumors. We have recently synthesized a novel class of
spermine analogues, the lead compound of which has efficacy against human
cancer cells (P. S. Callery et al., U. S. patent, 5,612,239, Issued March 17, 1997.). In this study, to investigate the potential therapeutic efficacy of the lead
spermine analogue 1,12-diaziridinyl-4, 9-diazadodecane (BIS), against advanced
prostate cancer, we examined the in vitro effect and in 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 against
prostate cancer cells via induction of apoptosis. Treatment of cells with BIS (1 microM) for 24 h resulted in a significant induction of apoptosis (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. Furthermore, BIS treatment led to a significant enhancement of loss of clonogenic survival in irradiated
prostate cancer cells (both PC-3 and DU-145). In vivo efficacy trials demonstrated a significant antitumor effect of BIS against both PC-3 and DU-145
tumor xenografts in severe combined immunodeficient mice in a dose-dependent pattern at maximally tolerated doses. Terminal
transferase end-labeling analysis indicated that BIS-mediated
tumor regression in vivo occurs via induction of apoptosis among prostatic
tumor cells. These results suggest that the novel
spermine analogue BIS: (a) has a potent antitumor effect against prostatic
tumors via induction of apoptosis; and (b) increases the radiosensitivity of human
prostate cancer cells by decreasing the apoptotic threshold to radiation. This study may have important clinical implications for the manipulation of this antitumor activity of the
polyamine analogue for the optimization of the therapeutic efficacy of radiation in patients with advanced
prostate cancer.