A comparison of the cytological effects of three hypoxic cell radiosensitizers
Misonidazole has entered Phase III clinical trials as a hypoxic cell radiosensitizer. Neurotoxocity is the major dose-limiting factor and has prompted the development of two further compounds with reduced lipophilicity and shorter half-life in vivo. Aside from the short-term problem of neurotoxicity, other potential long-term consequences should be considered. Such is the purpose of this investigation where the cytological effects of three radiosensitizers upon oxic and hypoxic Chinese hamster V-79 cells have been examined. Two newer compounds, desmethylmisonidazole and Stanford Research compound 2508, were compared with their clinically used predecessor misonidazole. Under aerated conditions, cell killing was increased with SR-2508 in a concentration and time dependent manner, so as to exceed by more than three times the level produced by the other two drugs at 5 mM for 72 hours.Cell progression into mitosis was also markedly reduced by as much as 1/10,000 of control values. However, as the three compounds induced similar frequencies of sister chromatid exchange (SCE) and chromosome aberration, the enhanced cytotoxic effect of SR-2508 appears to be mediated via an interphase rather than a post-mitotic cell death. Cells were made hypoxic and treated with the three drugs for 4 hr, then mitoses sequentially collected for 16 hr. The three compounds produced similar levels of cell killing, slowing of cell cycle progression, SCE's and chromosome aberrations, with cycle-specific effect on S and G-I phase cells for SCE induction. These results indicate that desmethylmisonidazole and misonidazole have similar cytotoxic and clastogenic properties under oxic and hypoxic conditions. SR-2508 is relatively more toxic to aerated cells and may deserve close clinical observation for toxicity to normal tissues.
- Research Organization:
- Columbia Univ. Coll. of Physicians and Surgeons, New York, NY
- OSTI ID:
- 6721582
- Journal Information:
- Int. J. Radiat. Oncol., Biol. Phys.; (United States), Vol. 8:7
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
ANTINEOPLASTIC DRUGS
BIOLOGICAL EFFECTS
COMPARATIVE EVALUATIONS
RADIOSENSITIZERS
ANIMAL CELLS
ANOXIA
CELL CYCLE
CELL KILLING
CHROMOSOMAL ABERRATIONS
DNA
IMIDAZOLES
MISONIDAZOLE
MITOSIS
MUTAGENESIS
NERVOUS SYSTEM
SISTER CHROMATID EXCHANGES
TOXICITY
AZOLES
CELL DIVISION
DRUGS
HETEROCYCLIC COMPOUNDS
MUTATIONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
560301* - Chemicals Metabolism & Toxicology- Cells- (-1987)