Radiosensitization of Hypoxic Tumor Cells by Simultaneous Administration of Hyperthermia and Nitroimidazoles

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Abstract
The radiation response of oxygenated and hypoxic L1210 [mouse] leukemia cells subjected to in vivo treatments with hyperthermia and/or chemical radiosensitizers was evaluated with the [125]iododeoxyuridine prelabeling assay. X-irradiation of L1210 cells at body temperatures of 41.degree. C or higher resulted in enhanced tumor cell death. The magnitude of this thermal effect increased with increasing temperatures. Hypoxic L1210 cells were particularly sensitive to heat induced enhancement of radiation damage, i.e., the sensitizing effects were more pronounced and occurred at lower temperatures. Chemical radiosensitizers (metronidazole, Ro-07-0582 [-(2-nitro-1-imidazolyl-)-3-methoxy-2-propanol]) selectively sensitized hypoxic L1210 populations. Fully oxygenated cells were not affected. Considerable radiosensitization was achieved at nontoxic dose levels of the 2 sensitizers. Experiments designed to determine the degree of radiosensitization as a function of drug dose showed that Ro-07-0582 was consistently more effective than metronidazole in sensitizing hypoxic tumor populations. At the highest drug used (3 mg/g body weight) the DMF [dose modifying factor] was 2.2 for metronidazole and 2.8 for Ro-07-0582. Combined administration of hyperthermia and Ro-07-0582 (or metronidazole) produced synergistic potentiation of radiation damage in hypoxic L1210 populations (DMF of 4.2). Under optimal conditions, hypoxic L1210 cells subjected simultaneously to both modes of radiosensitization became more radiosensitive than untreated, fully oxygenated L1210 cells. Experiments on 2 other tumor lines (BP-8 sarcoma and Ehrlich ascites cells) indicate that such synergistic radiosensitization effects are not unique to L1210 cells.