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Azomycin Riboside, a Sugar Homologue of Misonidazole with Favorable Radiosensitizing Properties¹

Cancer Research Unit (McEachern Laboratory) [S. M. J., A. R. P. P.] and Department of Chemistry [P. J. B.], University of Alberta, Edmonton T6G 2H7, and Department of Radiation Oncology, Cross Cancer Institute, Edmonton, T6G 1Z2 [J. D. C., J. N. L., K. A. R.] Alberta, Canada

Azomycin riboside, a congener of the radiosensitizing agent, misonidazole, sensitized hypoxic V79 hamster lung fibroblast cells to radiation and was cytotoxic to these cells. Radiosensitization effectiveness depended on the conditions of hypoxic cell exposure to azomycin riboside (concentration of the latter, time, and temperature). Cytotoxic and radiosensitizing effects resulting from exposure to azomycin riboside under anaerobic conditions were not manifested under aerobic conditions. The results presented demonstrate that azomycin riboside is an hypoxic cell radiosensitizer with effectiveness similar to or slightly better than misonidazole under in vitro conditions. The aglycone, azomycin, was weakly cytotoxic and a poor radiosensitizer in the V79 cell system. We have tested the idea that the differences in the efficacies of azomycin and its riboside as hypoxic cell radiosensitizers may be qualitatively related to the "transportability" of these agents by the nucleoside transport mechanism, that is, to their acceptance as substrates for that membrane transport system. Azomycin riboside, but not the aglycone, was shown to be a substrate for the nucleoside transport mechanism in human erythrocytes by demonstrating that exposure to azomycin riboside (a) induced inward countertransport of thymidine and (b) competitively inhibited thymidine influx in these cells. That V79 cells possess a functional nucleoside transport mechanism was evident in the demonstration of the binding of nitrobenzylthioinosine, a potent inhibitor of nucleoside transport, to high-affinity cellular sites under oxic and hypoxic conditions. Nitrobenzylthioninosine did not impair radiosensitization by azomycin riboside, suggesting that the transporter-mediated entry of azomycin riboside into cells was not a determinant of the radiosensitizing effect under conditions of the assay for that effect. The basis of the contribution of the ribosyl group to the radiosensitizing effect remains uncertain.

¹ This work was supported by the National Cancer Institute of Canada and the Cancer Research Grants Program (Alberta Cancer Board) of the Alberta Heritage Savings Trust Fund.

² Research Fellow, Cancer Research Grants Program (Alberta Cancer Board) of the Alberta Heritage Savings Trust Fund.

³ Present address: Chiron, Suite Q214, 4560 Horton St., Emeryville, Calif. 94608.

⁴ To whom requests for reprints should be addressed.

Received 11/23/81. Accepted 8/ 2/82.