The mitomycin bioreductive antitumor agents: Cross-linking and alkylation of DNA as the molecular basis of their activity

This review focuses on the chemical and enzymatic aspects of the reductive activation of mitomycin C, its disulfide analogs KW-2149 and BMS-181174, and, in less detail, FR66979 and FR900482, newly discovered antitumor antibiotics related to mitomycins. Furthermore, structural aspects of DNA damage i...

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Bibliographic Details
Published in:Pharmacology & therapeutics (Oxford) 1997-10, Vol.76 (1), p.73-87
Main Authors: Tomasz, Maria, Palom, Yolanda
Format: Article
Language:English
Subjects:
Alkylation - drug effects
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - therapeutic use
bioreductive
Biotransformation
Cross-Linking Reagents
DNA - chemistry
DNA - drug effects
DNA adducts
DNA cross-linking
DNA Damage - drug effects
Humans
Mitomycin
Mitomycins - chemistry
Mitomycins - metabolism
Mitomycins - therapeutic use
mitosene
Neoplasms - drug therapy
Neoplasms - genetics
Oxidation-Reduction
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Summary:This review focuses on the chemical and enzymatic aspects of the reductive activation of mitomycin C, its disulfide analogs KW-2149 and BMS-181174, and, in less detail, FR66979 and FR900482, newly discovered antitumor antibiotics related to mitomycins. Furthermore, structural aspects of DNA damage induced by these drugs in vitro and in vivo are described, including the chemical and conformational characteristics of DNA interstrand and intrastrand cross-links and monofunctional alkylation products, with emphasis on DNA adducts of mitomycin C. The DNA sequence specificity of the damage and its mechanism is reviewed. The relationship between the chemical and structural properties of the DNA damage on the one hand, and the antitumor and other biological activities of the mitomycins on the other, is discussed.
ISSN:0163-7258
1879-016X
DOI:10.1016/S0163-7258(97)00088-0