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 anticancer 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 metastases and different combinations of recombinant FGF induced a 7- to 15-fold doxorubicin resistance. Suramin had no effect on the doxorubicin activity in the absence of CM or FGF, but reversed the CM- and FGF-induced resistance by > or =90% at concentrations that had no cytotoxicity (i.e., 1-17 microM suramin). In the in vivo study, immunodeficient mice bearing well established, subcutaneous PC3 tumors (approximately 100 mg in size) 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 microM, had neither antitumor activity nor toxicity. Doxorubicin alone reduced tumor growth rate by approximately 60%, reduced the density of nonapoptotic tumor cells by approximately 60%, enhanced the apoptotic cell fraction by 4-fold, and reduced the body weight by approximately 15% (p < 0.05 compared with control). Addition of suramin to doxorubicin therapy did not increase weight loss but significantly enhanced the antitumor effect, resulting in complete inhibition of tumor growth, an additional 3-fold reduction in the density of nonapoptotic tumor cells, and an additional 2-fold enhancement of the apoptotic tumor cell fraction (p < 0.05 compared with all other groups). These data indicate significant enhancement of the effectiveness of doxorubicin in prostate tumors by nontoxic and subtherapeutic doses of suramin.
Zhang
Y
Y
College of Pharmacy and James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus 43210, USA.
Song
S
S
Yang
F
F
Au
J L
JL
Wientjes
M G
MG
D000465:Algorithms; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017077:Culture Media, Conditioned; D004317:Doxorubicin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013498:Suramin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D013498:Suramin; D004317:Doxorubicin