Low-dose suramin enhanced paclitaxel activity in chemotherapy-naive and paclitaxel-pretreated human breast xenograft tumors.

Abstract

We reported induction of broad-spectrum chemoresistance by acidic and basic fibroblast growth factors and chemosensitization by their nonspecific inhibitor suramin at nontoxic and subtherapeutic doses. This study evaluated whether low-dose suramin enhances paclitaxel activity in chemotherapy-naïve and paclitaxel-pretreated human MCF7 breast xenograft tumors in mice. Suramin, 10 mg/kg, and/or paclitaxel, 15 mg/kg, were administered intravenously, twice weekly for 2 to 3 weeks. In addition to conventional end points [tumor size change, median survival time (MST)], we also used clinically relevant end points [partial (PR) and complete response rates (CR); progressive disease (PD); stable disease (SD); time to tumor progression (TTP)]. In chemotherapy-naïve mice, the control and suramin groups showed identical TTP (3 days) and MST (21 days). Single-agent paclitaxel produced 47% PR and 24% CR, and prolonged both TTP and MST to 73 days. The addition of suramin further improved the total response rate to 100% with a dramatically greater 63% CR, shortened the time to attain PR and CR, and prolonged TTP and MST to > or =136 days. In the paclitaxel-pretreated group, single-agent paclitaxel resulted in 67% SD and 33% PD, whereas the combination produced 50% PR and 50% SD. Suramin also significantly enhanced the apoptotic effect of paclitaxel in tumors. In conclusion, suramin improved the activity of paclitaxel in both chemotherapy-naïve and paclitaxel-pretreated animals, without enhancing host toxicity (< or =10% body weight loss in all groups). These data have led to the initiation of phase I/II trials of paclitaxel and low-dose suramin combination in advanced metastatic breast cancer patients.