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-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; thus a therapeutic gain was achieved with RB-6145 in a murine tumor model.

• Authors: S Cole, I J Stratford, G E Adams, E M Fielden, T C Jenkins
• Journal: Radiation research (Radiat Res) Vol. 124 Issue 1 Suppl Pg. S38-43 (Oct 1990) ISSN: 0033-7587 [Print] United States
• PMID: 2236508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-nitro-1-imidazoly)-3-(2,3-dimethylaziridino)-2-propanol
• Antineoplastic Agents
• Prodrugs
• Radiation-Sensitizing Agents
• RB 7040
• 1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol
• Misonidazole

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Female
• Mice
• Mice, Inbred C3H
• Misonidazole (analogs & derivatives, therapeutic use)
• Prodrugs (therapeutic use)
• Radiation-Sensitizing Agents (therapeutic use)
• Sarcoma, Experimental (drug therapy, radiotherapy)