title: Rationale for phase I study of UFT plus leucovorin and oral JM-216.
abstract: Both cisplatin (Platinol) and fluorouracil (5-FU) have demonstrated single-agent clinical efficacy in a variety of solid neoplasms. The combination of these agents has revealed synergistic cytotoxicity in models in vitro and in vivo, which may explain the clinical effectiveness of 5-FU-cisplatin regimens. UFT (tegafur and uracil) and bis-aceto-ammine-dichloro-cyclohexyl-amine platinum(IV)(JM-216) are novel oral analogues of 5-FU and cisplatin, respectively. In preclinical models, JM-216 has demonstrated equivalent cytotoxicity to cisplatin, while phase I trials suggest its dose-limiting toxicity is myelosuppression. In contrast to cisplatin, JM-216 has not demonstrated significant neurotoxicity or nephrotoxicity. UFT has been used extensively in Japan, where phase II data suggest disease response rates similar to single-agent 5-FU in colorectal, gastric, and breast carcinomas. Combination studies of prolonged administration UFT and single-dose cisplatin have shown efficacy, but also significant hematologic toxicity. We propose a phase I study of UFT and JM-216 administered daily over 14 consecutive days with leucovorin (90 mg/d). Ease of administration and continuous drug exposure are potential advantages of this regimen. Several disease specific investigations may be warranted given demonstrated feasibility in this phase I study.
authors.affiliation: Department of Medicine, University of Chicago Medical Center, Illinois, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: DeMario
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000284:Administration, Oral; D000931:Antidotes / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000737:chemistry; D005641:Tegafur / Q000627:therapeutic use*; D014498:Uracil / Q000627:therapeutic use*
chemical_list: D000931:Antidotes; D004338:Drug Combinations; D009944:Organoplatinum Compounds; C096910:UFT(R) drug; D005641:Tegafur; D014498:Uracil; C081294:satraplatin; D002945:Cisplatin; D002955:Leucovorin