Low concentrations of nitroimidazoles: Effective radiosensitizers at low doses

• Published in: International journal of radiation oncology, biology, physics Vol. 29; no. 1; pp. 87 - 93
• Main Authors: Skov, Kirsten A., Macphail, Susan
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 30.04.1994; Elsevier
• Subjects: Animals; AZOLES; Biological and medical sciences; CHO Cells; COMPARATIVE EVALUATIONS; Cricetinae; DOSE-RESPONSE RELATIONSHIPS; DRUGS; Etanidazole; Etanidazole - administration & dosage; EVALUATION; HETEROCYCLIC COMPOUNDS; Hypoxia; IMIDAZOLES; In Vitro Techniques; Low doses; Medical sciences; Misonidazole; Misonidazole - administration & dosage; Nimorazole; Nimorazole - administration & dosage; NITRO COMPOUNDS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; PERFORMANCE TESTING; Radiation therapy and radiosensitizing agent; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT; Radiation-Sensitizing Agents - administration & dosage; RADIOSENSITIZERS; TESTING 560120 > Radiation Effects on Biochemicals, Cells, & Tissue Culture; Treatment with physical agents; Treatment. General aspects; Tumors; Radiosensitizers; Hypoxia; Low doses; Nimorazole; Misonidazole; Etanidazole; Imidazole derivatives; Radiation dose; Ionizing irradiation; Radiosensitizing agent; Animal; Established cell line; V79-Cell line; Concentration; Biological effect; Radiotherapy; In vitro; CHO cell line
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/0360-3016(94)90230-5

Purpose : There have been various reports that nitroimidazole radiosensitizers are less effective modifiers of radiation response in the clinically relevant x-ray dose regions (0–4 Gy) than they are at doses used in classical in vitro experiments. Our studies at low concentrations of etanidazole led us to question this generalization, and our purpose was to further investigate low concentrations at low doses, using the microscopic location of cells to facilitate these experiments. The observations are compared with data on these drugs in the literature using other methods and systems. Methods and Materials : Survival of V79 cells after irradiation in hypoxia ± drug at various concentrations was assessed using the Cell Analyser (DMIPS) for low doses, in comparison with the standard clonogenic assay (higher doses). Enhancement ratios (ERs) were calculated at 80% and 2% survival, respectively. Results : Etanidazole (SR-2508) consistently gave higher ERs at low doses (measured at 80% survival) than at high doses (survival 2%), when cells were exposed to drug concentrations below ∼ 2 mM (e.g., at 1 mM, ER 80% = 2.2, ER 2% = 1.8 in CHO cells after 1 h preincubation at 37°C). Preincubation of cells for 1 h or 15 min at 37°C with etanidazole prior to irradiation increased the ERs at high and low doses but did not change the “cross-over” behavior (ER 80% > ER 2% at low concentrations, ER 2% > ER 80% above 2 mM, regardless of pretreatment at 37°C or cell line, CHO and V79 cells), whereas the 5-nitroimidazole nimorazole consistently gave the same ERs whether determined at high or low radiation doses (e.g., at 1 mM, 1 h preincubation at 37°C ER 80% = ER 2% = 1.3). This crossover behavior also occurred after irradiation/preincubation at 0°C. The 2-nitroimidazole predecessor, misonidazole, shows the same cross-over behavior. Conclusion : Two nitroimidazoles at low concentrations appear to be as effective sensitizers (or better) at low doses (80% S); at high doses (2% S).