title: Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study.
abstract: BACKGROUND
  The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients.
  
  
  METHODS
  Patients received paclitaxel (Taxol) (200 mg/m(2)) and carboplatin (area under the concentration-time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10-50 microM.
  
  
  RESULTS
  Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 microM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for > or =4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for > or =4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M).
  
  
  CONCLUSIONS
  Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.
authors.affiliation: Department of Medicine, Pharmacology and College of Pharmacy, The Ohio State University, The Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210-1240, USA. miguel.villalona@osumc.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: G A
authors.initials: GA
authors.lastname: Otterson
authors.forename: M G
authors.initials: MG
authors.lastname: Wientjes
authors.forename: F
authors.initials: F
authors.lastname: Weber
authors.forename: T
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: D
authors.initials: D
authors.lastname: Young
authors.forename: A J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: R
authors.initials: R
authors.lastname: Jensen
authors.forename: T-K
authors.initials: TK
authors.lastname: Yeh
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.forename: M
authors.initials: M
authors.lastname: Grever
authors.forename: J L-S
authors.initials: JL
authors.lastname: Au
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000097:blood; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013498:Suramin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D013498:Suramin; D016190:Carboplatin; D017239:Paclitaxel