title: 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 microg/kg intravenously) for 4 weeks. The optimal interlude between the administration of suramin and bFGF-SAP was determined by tumor 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 mm(3)). TGI observed for combination therapies varied significantly (P<0.05-0.001) from TGI observed in treatment groups receiving suramin alone (57%) or bFGF-SAP alone (34-38%). Combining bFGF-SAP (5 microg/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.
authors.affiliation: Department of Medicine, Roger Williams Medical Center and Brown University, Providence, Rhode Island 02908, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Davol
authors.forename: S
authors.initials: S
authors.lastname: Garza
authors.forename: A R
authors.initials: AR
authors.lastname: Frackelton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004359:Drug Therapy, Combination; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010940:Plant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013498:Suramin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C078442:basic fibroblast growth factor-saporin mitotoxin, recombinant; D016222:Fibroblast Growth Factor 2; D013498:Suramin; D000076985:Saporins