A new potent radiosensitizer: 1-(2',3'-dideoxy-. cap alpha. -D-erythro-hex-2'-enopyranosyl)-2-nitroimidazole (RA-263)

Journal Article · Mon Mar 01 04:00:00 EST 1982 · Int. J. Radiat. Oncol., Biol. Phys.; (United States)

DOI:https://doi.org/10.1016/0360-3016(82)90648-4· OSTI ID:6715141

Agrawal, K C ^[1]; Sakaguchi, M; Rockwell, S

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1. Tulane Univ. School of Medicine, New Orleans, LA

Among a series of 2-nitroimidazole nucleosides synthesized, 1-(2', 3'-dideoxy-..cap alpha..-D-erythro-hex-2'-enopyranosyl)-2-nitroimidazole (RA-263) was found to be one of the most effective radiosenitizers. Exponentially growing asynchronous Chinese hamster (V-79) cells were employed for in vitro toxicity tests and radiation survival curves. Although RA-263 was nontoxic to the oxic V-79 cells at a concentration of 1 mM up to 4 hr exposure, cell growth was completely inhibited of the hypoxic cells under these conditions. The ..beta..-isomer of RA-263 was comparatively less cytotoxic to the hypoxic cells since 43% cells survived under similar conditions. RA-263 produced an enhancement ratio (ER) of 2.0 at 0.5 mM, higher concentrations markedly suppressed the shoulder region of the radiation cell survival curve and produced a significant increase in radiosensitization. The acute LD/sub 50/ of RA-263 in CDF/sub 1/ mice was found to be 3.3 g/kg, indicating that RA-263 is approximately 2.5 times less toxic than misonidazole. Pharmacokinetic studies in C57 mice bearing B16 melanoma produced a favorable tumor/plasma ratio of 0.88 and brain/plasma ratio of 0.16 after 30 min at the dose level of 1 mg/g administered intraperitoneally. In vivo radiosensitization studies in BALB/c mice bearing EMT6 mammary tumor indicate that RA-263 is as effective a sensitizer as misonidazole at an equivalent dose of 1 mg/g. Increasing the dose of RA-263 to 2 mg/g caused a significant increase in radiosensitization. These data suggest that RA-263 may be superior to misonidazole as a radiosensitizer for potential clinical use.

• OSTI ID: 6715141
• Journal Information: Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 8:3/4; 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
ANIMALS
AZOLES
BIOLOGICAL EFFECTS
BIOLOGICAL RADIATION EFFECTS
CELL CULTURES
CELL KILLING
CONNECTIVE TISSUE CELLS
DISEASES
DOSES
DRUGS
EXPERIMENTAL NEOPLASMS
FIBROBLASTS
HAMSTERS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
LETHAL DOSES
MAMMALS
MELANOMAS
MICE
NEOPLASMS
NITRO COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
RADIATION EFFECTS
RADIOINDUCTION
RADIOSENSITIVITY EFFECTS
RADIOSENSITIZERS
RODENTS
SOMATIC CELLS
SURVIVAL CURVES
VERTEBRATES