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Title: Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas

Abstract

The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144more » was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069.« less

Authors:
; ; ; ;  [1]
  1. Medical Research Council, Didcot, Oxon (England)
Publication Date:
OSTI Identifier:
6167404
Resource Type:
Journal Article
Journal Name:
Radiation Research; (USA)
Additional Journal Information:
Journal Volume: 124:1 Suppl; Journal ID: ISSN 0033-7587
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; 62 RADIOLOGY AND NUCLEAR MEDICINE; RADIOSENSITIZERS; TOXICITY; SARCOMAS; COMBINED THERAPY; ANTINEOPLASTIC DRUGS; DOSE-RESPONSE RELATIONSHIPS; EXPERIMENTAL NEOPLASMS; MICE; RADIATION DOSES; RADIOSENSITIVITY EFFECTS; X RADIATION; ANIMALS; DISEASES; DOSES; DRUGS; ELECTROMAGNETIC RADIATION; IONIZING RADIATIONS; MAMMALS; NEOPLASMS; RADIATIONS; RODENTS; THERAPY; VERTEBRATES; 560152* - Radiation Effects on Animals- Animals; 550603 - Medicine- External Radiation in Therapy- (1980-)

Citation Formats

Cole, S, Stratford, I J, Adams, G E, Fielden, E M, and Jenkins, T C. Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas. United States: N. p., 1990. Web. doi:10.2307/3577675.
Cole, S, Stratford, I J, Adams, G E, Fielden, E M, & Jenkins, T C. Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas. United States. doi:10.2307/3577675.
Cole, S, Stratford, I J, Adams, G E, Fielden, E M, and Jenkins, T C. Mon . "Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas". United States. doi:10.2307/3577675.
@article{osti_6167404,
title = {Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas},
author = {Cole, S and Stratford, I J and Adams, G E and Fielden, E M and Jenkins, T C},
abstractNote = {The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069.},
doi = {10.2307/3577675},
journal = {Radiation Research; (USA)},
issn = {0033-7587},
number = ,
volume = 124:1 Suppl,
place = {United States},
year = {1990},
month = {10}
}