Combining suramin and a chimeric toxin directed to basic fibroblast growth factor receptors increases therapeutic efficacy against human melanoma in an animal model

Abstract

BACKGROUND. Suramin, which binds to and blocks autocrine and paracrine growth factors required for the proliferation of neoplastic cells, is a clinically effective antitumor agent against some human tumors; however, efficacy often is limited by toxicity. In this study, suramin treatment was combined with a fibroblast growth factor (FGF) receptor-directed toxin chimera, basic FGF-saporin (bFGF-SAP), based on the authors' previous observations that autocrine-mediated resistance to bFGF-SAP in melanoma in vitro is abrogated by suramin treatment. METHODS. Severe-combined immunodeficient-Beige mice bearing SK-Mel-5 human melanoma xenografts received weekly treatments of suramin (200 or 75 mg/kg intraperitoneally) beginning on Day 5 after tumor implantation followed 18 hours later by a treatment with bFGF-SAP [0.5-5 μg/kg intravenously) for 4 weeks. The optimal interlude between the administration of suramin and bFGF-SAP was determined by rumor excision assays. The efficacy of combination therapy as a function of alternative dosing regimens was determined by tumor growth inhibition (TGI) studies. RESULTS. Fifty days after implantation, a 79-82% TGI was observed in animals receiving the suramin (200 mg/kg) plus bFGF-SAP combination regimens compared with median tumor volumes from vehicle-treated controls (3070 ± 440 mm3). TGI observed for combination therapies varied significantly (P < 0.050.001) from TGI observed in treatment groups receiving suramin alone (57%) or bFGF-SAP alone (34-38%). Combining bFGF-SAP (5 μg/kg) with a low, therapeutically ineffective dose of suramin (75 mg/kg) produced a 68% rate of TGI compared with controls, thus lowering the therapeutic effective dose of suramin and eliminating the suramin-related lethal toxicity (12% mortality rate) observed in animals treated with high dose suramin. CONCLUSIONS. The results of the current study suggest that combining suramin with receptor-directed therapies offers a more effective regimen for the treatment of malignant melanoma.