Nontoxic doses of suramin enhance activity of doxorubicin in prostate tumors

We recently reported that acidic and basic fibroblast growth factors (aFGF and bFGF) confer a broad-spectrum chemoresistance in solid tumors, and that inhibitors of these proteins enhanced the antitumor activity of several an ticancer drugs. The present study investigated the effect of FGF inhibitors on doxorubicin activity in human prostate PC3 tumors. In in vitro studies, conditioned medium (CM) obtained from histocultures of rat MAT-LyLu lung m etastases and different combinations of recombinant FGF induced a 7- to 15- fold doxorubicin resistance. Suramin had no effect on the doxorubicin activ ity in the absence of CM or FGF, but reversed the CM- and FGF-induced resis tance by greater than or equal to 90% at concentrations that had no cytotox icity (i.e., 1-17 muM suramin). In the in vivo study, immunodeficient mice bearing well established, subcutaneous PC3 tumors (similar to 100 mg in siz e) were treated intravenously with doxorubicin (5 mg/kg) and suramin (10 mg /kg), administered twice weekly for 3 weeks. The suramin dose, selected to yield plasma concentration of below 50 muM, had neither antitumor activity nor toxicity. Doxorubicin alone reduced tumor growth rate by similar to 60% , reduced the density of nonapoptotic tumor cells by similar to 60%, enhanc ed the apoptotic cell fraction by 4-fold, and reduced the body weight by si milar to 15% (p < 0.05 compared with control). Addition of suramin to doxor ubicin therapy did not increase weight loss but significantly enhanced the antitumor effect, resulting in complete inhibition of tumor growth, an addi tional 3-fold reduction in the density of nonapoptotic tumor cells, and an additional 2-fold enhancement of the apoptotic tumor cell fraction (p < 0.0 5 compared with all other groups). These data indicate significant enhancem ent of the effectiveness of doxorubicin in prostate tumors by nontoxic and subtherapeutic doses of suramin.