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Radiosensitizing and toxic effects of Ro-07-0582 in hypoxic mammalian cells Moore, Brian A.


Cells experiencing a low oxygen tension show relative resistance to the lethal effects of radiation. It is believed that the effectiveness of the treatment of certain human tumors is hindered by the existence of such radioresistant cells within the tumor. The purpose of this work was to study the drug Ro-07-0582 both for its toxic effects and its ability to preferentially sensitize hypoxic cells to the lethal effects of radiation (radiosensitize). These properties were examined in vitro in two Chinese hamster cell lines, CHO and CH2B2, and also in the mouse tumour cell line EMT6. Ro-07-0582 is shown to have a chemotherapeutic potential in that it demonstrates a very selective toxicity for hypoxic cells after a few hours exposure. It is much less toxic to aerobic cells. These toxic properties were studied extensively, both in hypoxic and aerobic cell suspensions. The measured endpoint was the ability of a cell to multiply and form a colony of 50 or more cells within an allotted incubation time. Hypoxic toxicity was greater at 37°C than at 22°C and was affected by small changes (~30ppm) in 0₂ concentration in the cell suspension. The toxic effects were similar in the three cell lines. The radiosensitizing capability of Ro-07-0582 was determined by measuring the Dose Modifying Factors (DMF's) for various drug concentrations with each cell line. DMF's were calculated by comparison of survival curves for cell suspensions irradiated under hypoxia in the presence of drug with the survival curve for cell suspensions irradiated under hypoxia in the absence of drug. The DMF for the irradiation of aerobic cells in the absence of drug is called the Oxygen Enhancement Ratio (OER) and was approximately 3.0 in all three cell lines. Ro-07-0582 was found to selectively radiosensitize hypoxic cells in suspension with high efficiency. For each cell line, sensitization was observed with drug concentrations as low as 0.1mM, while concentrations of 10mM or greater yielded DMF's within the measured range of OER values. The presence of 1mM Ro-07-0582 during irradiation of hypoxic cells yields a DMF of 1.8. Introduction of the drug before or after irradiation, instead of during irradiation, had little if any effect. Radiosensitization measurements were also carried out at high cell concentrations (cell pellets), where many sensitizers are ineffective. Results showed that the 0582 radiosensitization attained in cell pellets is quite comparable with that attained in dilute suspension. The attributes of Ro-07-0582 as a potential radiosensi-tizer were considered. The sensitization achieved by Ro-07-0582 is very good, and surpasses that of metronidazole, a chemical under study for clinical use. For drug doses necessary to achieve high levels of sensitization the toxicity of Ro-07-0582 to aerobic cells is quite acceptable. The toxicity to hypoxic cells, however, is much increased over the toxicity to aerobic cells, and this may prove to be a useful adjunct to the drug's sensitizing properties in destroying hypoxic tumour cells.

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