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 s uramin, an inhibitor of multiple growth factors including aFGF and bFGF, en hanced the in vitro antitumor activity of several anticancer drugs includin g paclitaxel (Song, S., et al., Proc. Natl. Acad. Sci. USA, 97: 8658-8663, 2000). The present study investigated in vitro and in vivo interaction betw een paclitaxel and suramin, using human PC3-LN cells which, upon i.v. injec tion into immunodeficient mice, yielded lung metastases in 100% of animals. In in vitro studies, conditioned medium (CM) obtained from histocultures o f 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 IC50 values indicate a complete reversal in the p resence of < 20 muM suramin. Analysis by the combination index method indic ates a synergistic interaction between paclitaxel and suramin. In in vivo s tudies, animals with well-established lung metastases (at least five nodule s of 1 min in diameter) were treated i.v. with paclitaxel (15 mg/kg) and su ramin (10 mg/kg) administered twice weekly for 3 weeks. Single-drug therapy with paclitaxel or suramin did not reduce body weight. Suramin alone had n o antitumor activity. Paclitaxel alone reduced the tumor size by similar to 75%, reduced the density of nonapoptotic cells by similar to 70% in residu al tumors, and enhanced the fraction of apoptotic cells by similar to3-fold . The addition of suramin to paclitaxel therapy enhanced the antitumor effe ct, resulting in an additional 5-fold reduction of tumor size, an additiona l 9-fold reduction of the density of nonapoptotic cells, and an additional 30% increase in the apoptotic cell fraction. These data indicate significan t enhancement of the efficacy of paclitaxel by suramin and support the use of nontoxic doses of suramin with paclitaxel in the treatment of lung cance r.