Keynote address: cellular reduction of nitroimidazole drugs: potential for selective chemotherapy and diagnosis of hypoxic cells

Journal Article · Sat Apr 01 04:00:00 EST 1989 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(89)90886-9· OSTI ID:6097263

Chapman, J D; Lee, J; Meeker, B E

Nitroimidazole drugs were initially developed as selective radiosensitizers of hypoxic cells and, consequently, as adjuvants to improve the local control probabilities of current radiotherapies. Misonidazole (MISO), the prototype radiosensitizing drug, was found in Phase I clinical studies to cause dose-limiting neurotoxicities (mainly peripheral neuropathies). MISO was also found to be cytotoxic in the absence of radiation and to covalently bind to cellular molecules, both processes demonstrating rates much higher in hypoxic compared with oxygenated cells. It is likely that neurotoxicity, cellular cytotoxicity and adduct formation results from reactions between reduction intermediates of MISO and cellular target molecules. Spin-offs from radiosensitizer research include the synthesis and characterization of more potent hypoxic cytotoxins and the exploitation of sensitizer-adducts as probes for measuring cellular and tissue oxygen levels. Current developments in hypoxic cell cytotoxin and hypoxic cell marker research are reviewed with specific examples from studies which characterize the cellular reduction of TF-MISO, (1-(2-nitro-1-imidazolyl)-3(2,2,2-trifluoroethoxy)-2-propanol). 45 references.

• Research Organization: Cross Cancer Institute, Edmonton, Alberta (Canada)
• OSTI ID: 6097263
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 16:4; ISSN IOBPD
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANOXIA
ANTINEOPLASTIC DRUGS
AZOLES
BIOCHEMICAL REACTION KINETICS
DOCUMENT TYPES
DRUGS
EVALUATION
EXPERIMENTAL NEOPLASMS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
KINETICS
MEDICINE
MISONIDAZOLE
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RADIOLOGY
RADIOSENSITIZERS
RADIOTHERAPY
REACTION KINETICS
REVIEWS
THERAPY
TOXICITY
TUMOR CELLS