Hypoxia-specific inhibition of recovery from radiation damage by a novel 2-nitroimidazole with a theophylline side chain.
A novel 2-nitroimidazole with a theophylline side-chain, 7-(4'-(2-nitroimidazol-1-yl)-butyl)-theophylline, (NITP) was as efficient a hypoxic-cell radiosensitizer as misonidazole. However, if cells were irradiated with NITP under hypoxic conditions and then exposed to the drug under aerobic conditions, a much larger radiosensitizing effect was observed, partly because of a reduction in the size of the shoulder of the survival curve. There was little effect of NITP on the radiosensitivity of well oxygenated cells, even with post-irradiation drug contact. Split-dose survival curves showed that the drug inhibited recovery from radiation damage only when the cells were irradiated under hypoxia but not when irradiations were under oxic conditions. A reduction in the size of the shoulder of the survival curve should allow the hypoxic-cell radiosensitizing efficiency of NITP to be maintained with low doses of radiation used in multifraction cancer radiotherapy. Bifunctional drugs containing both electron-affinic and repair inhibiting groups may represent a new approach to the synthesis of hypoxic-cell targeted adjuncts to radiotherapy.
Hodgkiss
R J
RJ
Gray Laboratory of the Cancer Research Campaign, Mount Vernon Hospital, Northwood, Middlesex, U.K.
Kelleher
E
E
Parrick
J
J
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D008920:Misonidazole / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C075173:7-(4'-(2-nitroimidazole-1-yl)butyl)theophylline; D002110:Caffeine; D008920:Misonidazole; D013806:Theophylline