SR-2508: a 2-nitroimidazole amide which should be superior to misonidazole as a radiosensitier for clinical use

Journal Article · Mon Jun 01 04:00:00 EDT 1981 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(81)90460-0· OSTI ID:6298858

Brown, J M; Yu, N Y; Brown, D M; Lee, W W

Using a combination of toxicological, pharmacological and radiosensitization experiments on cells in vitro and tumors in vivo, we have selected two 2-nitroimidadole amides which should prove superior to misonidazole (MIS) for clinical use. The two drugs, SR-2508 and SR-2555, are considered to be close to the optimum for variants of misonidazole of the same electron affinity; their main difference is a lower lipophilicity than MIS. This lower lipophilicity leads to poorer penetration into neural tissues than that of MIS and this leads, as expected, to lower neurotoxicity of these drugs compared to MIS (as judged by an accelerating rotarod test following 4 to 5 weeks of daily injections). The in vitro radiosensitization tests on hypoxic Chinese hamster ovary HA-1 cells show that SR-2508 and MIS have the same radiosensitization efficiency but are slightly more potent as radiosensitizers than SR-2555. For the in vivo radiosensitization experiments we used the in vivo-in vitro cloning assay with the EMT6 tumor, the regrowth assay with RIF-1 and KHJJ tumors and the TCD/sub 50/ assay with the MDAH/MCa4 carcinoma. All show roughly equivalent levels of radiosensitization of both SR-2508 and SR-2555 to MIS although, as predicted by the in vitro results, SR-2555 is slightly inferior to SR-2508. We conclude that, although SR-2555 appears to be slightly less neurotoxic than SR-2508, its lower radiosensitizing efficacy is likely to make it less attractive than SR-2508 as a replacement for MIS for clinical use. Extrapolating the neurotoxicity data obtained in the mouse together with pharmacological studies of SR-2508 in spontaneous tumors of the dog, we estimate that levels of SR-2508 of at least 7.5 times those of MIS will be able to be achieved in human tumors for the equivalent level of neurotoxicity. This should enable essentially maximum radiosensitization of the hypoxic cells in human tumors to be obtained in conventional daily fractionation.

• OSTI ID: 6298858
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 7:6; ISSN IOBPD
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMAL TISSUES
ANTINEOPLASTIC DRUGS
AZOLES
BIOCHEMISTRY
BODY
CELL CULTURES
CHEMISTRY
CHEMOTHERAPY
CLONE CELLS
COMPARATIVE EVALUATIONS
DRUGS
EXTERNAL IRRADIATION
FRACTIONATED IRRADIATION
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
IN VITRO
IN VIVO
IRRADIATION
LABORATORY ANIMALS
MEDICINE
MISONIDAZOLE
NERVE TISSUE
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
RADIOLOGY
RADIOSENSITIVITY
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
RADIOTHERAPY
THERAPY
TISSUES
TOXICITY
TUMOR CELLS