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Sequential inhibition of polyamine synthesis. A phase I trial of DFMO (alpha-difluoromethylornithine) and methyl-GAG [methylglyoxal-bis(guanylhydrazone)].

Authors
  • Warrell, R P Jr
  • Coonley, C J
  • Burchenal, J H
Type
Published Article
Journal
Cancer chemotherapy and pharmacology
Publication Date
Jan 01, 1983
Volume
11
Issue
2
Pages
134–136
Identifiers
PMID: 6414731
Source
Medline
License
Unknown

Abstract

Both DFMO and methyl-GAG inhibit sequential enzymatic reactions in the pathway of polyamine biosynthesis. Since polyamines may be important factors in proliferation of cancer cells, we initiated a phase-I study of these agents in patients with advanced cancer. DFMO was given by mouth at a constant daily dose of 4 g/m2 starting on day 1 of the treatment protocol. The dose of methyl-GAG ranged from 200 to 700 mg/m2 administered IV every 2 weeks beginning on day 4. Twenty-two patients were entered into the protocol. Toxic reactions to this therapy were dose-related and included nausea, fatigue, diarrhea, and myelosuppression. One patient with colon cancer experienced a greater than 50% decrease in measurable disease but developed severe myelotoxicity. While DFMO was well tolerated, the combination of drugs appeared to cause substantially more hematologic and gastrointestinal toxicity than encountered during our recent experience with methyl-GAG used alone. We suggest that future studies of this drug combination carefully evaluate levels of polyamines and inhibition of enzymatic activity to minimize toxicity.

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