Nontoxic doses of suramin enhance activity of paclitaxel against lung metastases.
We recently reported that acidic (aFGF) and basic (bFGF) fibroblast growth factors confer a broad spectrum chemoresistance in solid tumors, and that suramin, an inhibitor of multiple growth factors including aFGF and bFGF, enhanced the in vitro antitumor activity of several anticancer drugs including paclitaxel (Song, S., et al., Proc. Natl. Acad. Sci. USA, 97: 8658-8663, 2000). The present study investigated in vitro and in vivo interaction between paclitaxel and suramin, using human PC3-LN cells which, upon i.v. injection into immunodeficient mice, yielded lung metastases in 100% of animals. In in vitro studies, conditioned medium (CM) obtained from histocultures of rat lung metastases induced a 3-fold resistance. The addition of suramin had no effect in the absence of CM but reversed the CM-induced resistance; calculations based on the IC(50) values indicate a complete reversal in the presence of <20 microM suramin. Analysis by the combination index method indicates a synergistic interaction between paclitaxel and suramin. In in vivo studies, animals with well-established lung metastases (at least five nodules of 1 mm in diameter) were treated i.v. with paclitaxel (15 mg/kg) and suramin (10 mg/kg) administered twice weekly for 3 weeks. Single-drug therapy with paclitaxel or suramin did not reduce body weight. Suramin alone had no antitumor activity. Paclitaxel alone reduced the tumor size by approximately 75%, reduced the density of nonapoptotic cells by approximately 70% in residual tumors, and enhanced the fraction of apoptotic cells by approximately 3-fold. The addition of suramin to paclitaxel therapy enhanced the antitumor effect, resulting in an additional 5-fold reduction of tumor size, an additional 9-fold reduction of the density of nonapoptotic cells, and an additional 30% increase in the apoptotic cell fraction. These data indicate significant enhancement of the efficacy of paclitaxel by suramin and support the use of nontoxic doses of suramin with paclitaxel in the treatment of lung cancer.
Song
S
S
College of Pharmacy and James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, Ohio 43210, USA.
Wientjes
M G
MG
Walsh
C
C
Au
J L
JL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017077:Culture Media, Conditioned; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D013498:Suramin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017077:Culture Media, Conditioned; D013498:Suramin; D017239:Paclitaxel