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 Citations (Scopus)

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 1995

Fingerprint

Vitamin K 3
Mitomycin
Tumors
Neoplasms
Hemolysis
Glutathione
Intravenous Infusions
Erythrocytes
Cells
Chemotherapy
Maximum Tolerated Dose
Vitamin K
Glucosephosphate Dehydrogenase
Alkylating Agents

Keywords

  • Menadione
  • Mitomycin C
  • Phase I studies

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Margolin, K. A., Akman, S. A., Leong, L. A., Morgan, R. J., Somlo, G., Raschko, J. W., ... 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

Phase I study of mitomycin C and menadione in advanced solid tumors. / Margolin, Kim A.; Akman, Steven A.; Leong, Lucille A.; Morgan, Robert J.; Somlo, George; Raschko, James W.; Ahn, Chul; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 36, No. 4, 07.1995, p. 293-298.

Research output: Contribution to journalArticle

Margolin, KA, Akman, SA, Leong, LA, Morgan, RJ, Somlo, G, Raschko, JW, Ahn, C & Doroshow, JH 1995, 'Phase I study of mitomycin C and menadione in advanced solid tumors', Cancer Chemotherapy and Pharmacology, vol. 36, no. 4, pp. 293-298. https://doi.org/10.1007/BF00689046
Margolin KA, Akman SA, Leong LA, Morgan RJ, Somlo G, Raschko JW et al. Phase I study of mitomycin C and menadione in advanced solid tumors. Cancer Chemotherapy and Pharmacology. 1995 Jul;36(4):293-298. https://doi.org/10.1007/BF00689046
Margolin, Kim A. ; Akman, Steven A. ; Leong, Lucille A. ; Morgan, Robert J. ; Somlo, George ; Raschko, James W. ; Ahn, Chul ; Doroshow, James H. / Phase I study of mitomycin C and menadione in advanced solid tumors. In: Cancer Chemotherapy and Pharmacology. 1995 ; Vol. 36, No. 4. pp. 293-298.
@article{c4896c54385c4a60841e29c8084566fc,
title = "Phase I study of mitomycin C and menadione in advanced solid tumors",
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.",
keywords = "Menadione, Mitomycin C, Phase I studies",
author = "Margolin, {Kim A.} and Akman, {Steven A.} and Leong, {Lucille A.} and Morgan, {Robert J.} and George Somlo and Raschko, {James W.} and Chul Ahn and Doroshow, {James H.}",
year = "1995",
month = "7",
doi = "10.1007/BF00689046",
language = "English (US)",
volume = "36",
pages = "293--298",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Phase I study of mitomycin C and menadione in advanced solid tumors

AU - Margolin, Kim A.

AU - Akman, Steven A.

AU - Leong, Lucille A.

AU - Morgan, Robert J.

AU - Somlo, George

AU - Raschko, James W.

AU - Ahn, Chul

AU - Doroshow, James H.

PY - 1995/7

Y1 - 1995/7

N2 - 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.

AB - 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.

KW - Menadione

KW - Mitomycin C

KW - Phase I studies

UR - http://www.scopus.com/inward/record.url?scp=0029067681&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029067681&partnerID=8YFLogxK

U2 - 10.1007/BF00689046

DO - 10.1007/BF00689046

M3 - Article

C2 - 7628048

AN - SCOPUS:0029067681

VL - 36

SP - 293

EP - 298

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -