Phase I study of mitomycin C and menadione in advanced solid tumors

Kim A. Margolin, Steven A. Akman, Lucille A. Leong, Robert J. Morgan, George Somlo, James W. Raschko, Chul Ahn, James H. Doroshow

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and 4.0 g/m2 over 48 h were associated with hemolysis, so subsequent dose levels of menadione ranged from 1.0 to 3.0 g/m2 with mitomycin C from 5 to 20 mg/m2. All three patients treated with menadione at 8.0 g/m2 and the single patient treated at 4.0 g/m2 with mitomycin C at 5 mg/m2 developed clinically significant hemolysis despite the presence of red blood cell glucose-6-phosphate dehydrogenase. Subsequently, a revised escalation scheme for menadione was used, and all patients tolerated menadione doses of 1-2.5 g/m2 over 48 h with mitomycin C doses up to 20 mg/m2. Since the 3.0 g/m2 dose of menadione was associated with mild hemolysis in three of four patients, the maximum tolerated dose of menadione was established at 2.5 g/m2. All of the mitomycin dose levels were tolerated without unexpected toxicities attributable to the combination. Prolonged infusions of menadione at doses which have been associated with lowering of intracellular glutathione pools in short-term exposure are limited by dose-dependent hemolysis, probably due to depletion of erythrocyte glutathione by menadione-related redox cycling. There was no detectable deleterious effect of pre-exposure to menadione on mitomycin C tolerance. We recommend a combination of menadione at 2.5 g/m2 as a continuous intravenous infusion and mitomycin C at 15 mg/m2 for further study in solid tumors for which treatment with single-agent mitomycin C is appropriate.

Original languageEnglish (US)
Pages (from-to)293-298
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume36
Issue number4
DOIs
StatePublished - Jul 1 1995

Keywords

  • Menadione
  • Mitomycin C
  • Phase I studies

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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  • Cite this

    Margolin, K. A., Akman, S. A., Leong, L. A., Morgan, R. J., Somlo, G., Raschko, J. W., Ahn, C., & Doroshow, J. H. (1995). Phase I study of mitomycin C and menadione in advanced solid tumors. Cancer Chemotherapy and Pharmacology, 36(4), 293-298. https://doi.org/10.1007/BF00689046