APOPTOSIS AND CLONOGENIC CELL-DEATH IN PC3 HUMAN PROSTATE-CANCER CELLS AFTER TREATMENT WITH GAMMA-RADIATION AND SURAMIN

Suramin is a novel cytostatic/cytotoxic agent that is currently underg oing clinical trials in the treatment of hormone- and chemo-refractory tumors. Its unusual mechanism of action and its activity against pros tate cancer raise the possibility that it could be particularly suitab le for combined-modality treatment of prostate cancer. PC3 human prost ate cancer tells were used as an in vitro model to test the possible i nteraction between suramin and ionizing radiation. Treatment with gamm a radiation resulted in detachment of PC3 cells from the monolayer, an d the detached cells exhibited internucleosomal DNA fragmentation char acteristic of apoptosis. Low concentrations of suramin (50-100 mu g/ml , 35-70 mu M) increased spontaneous as well as radiation-enhanced apop tosis. However, suramin inhibited spontaneous and radiation-enhanced a poptosis at 300 mu g/ml (210 mu M), a concentration that is more commo nly used in the clinic. At this concentration suramin inhibited DNA fr agmentation induced by chemotherapeutic drugs as well. The effect of s uramin on inhibition of DNA fragmentation was reversible if the surami n was removed 24 h after irradiation. Despite inhibition of radiation- induced apoptosis by 300 mu g/ml suramin (from 5% to 2.9% at 48 h), cl onogenic cell death was enhanced by the combination of suramin and rad iation. The effects of radiation and suramin on cIonogenic cell surviv al appeared to be additive by isobologram analysis at clinically relev ant radiation doses. Continuous exposure to a lower concentration of s uramin (100 mu g/ml) during the clonogenic assay period was as effecti ve in decreasing clonogenic survival as 48 h exposure to 300 mu g/ml s uramin in decreasing clonogenic survival. Our data indicate that, when used in combination with radiation, suramin may be effective at conce ntrations that are lower than those required for efficacy as a single agent. (C) 1997 bg Radiation Research Society.