title: Enhancement of the clinical activity of melphalan by the hypoxic cell sensitizer misonidazole.
abstract: One hundred patients with non-small cell lung cancer were entered by members of the Northern California Oncology Group into a randomized Phase II trial of i.v. melphalan versus i.v. melphalan with concomitant oral misonidazole. The patients had not received prior chemotherapy. Eighty-five patients were evaluable for assessment of response and 89 were evaluable for toxicity analysis. The melphalan/misonidazole group had a superior response rate (two complete and four partial responses among 42 patients or 14%) compared to the melphalan group in which there were no responses among 43 patients (p = 0.024, two-sided Fisher exact test). Since hematological toxicity was equivalent in the two groups, there was an improvement in therapeutic index. Data from 12 patients undergoing pharmacological studies demonstrated that the plasma concentration of melphalan was 25% higher in the misonidazole group, a difference that is not statistically significant. Although the mechanism of interaction has not been fully established, this randomized trial demonstrates that a chemosensitizer can enhance the clinical antitumor activity of an alkylating agent and suggests that chemosensitizers in combination with alkylating agents should be investigated in further clinical trials.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, California.
authors.forename: C N
authors.initials: CN
authors.lastname: Coleman
authors.forename: R W
authors.initials: RW
authors.lastname: Carlson
authors.forename: R A
authors.initials: RA
authors.lastname: Artim
authors.forename: W I
authors.initials: WI
authors.lastname: Sampson
authors.forename: H J
authors.initials: HJ
authors.lastname: Lawrence
authors.forename: P
authors.initials: P
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Halsey
authors.forename: M
authors.initials: M
authors.lastname: Kohler
authors.forename: M
authors.initials: M
authors.lastname: Gribble
authors.forename: B I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D008920:Misonidazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D008920:Misonidazole; D008558:Melphalan