A multidisciplinary effort is underway to design and synthesize (a) an antineoplastic agent effective against solid tumors and (b) a radiosensitizing agent for selective sensitization of hypoxic tumor cells towards treatment with ionizing radiation. A major effort will be directed toward development of cytotoxic agents designed specifically to kill the hypoxic cells present in solid tumors. This will be achieved by utilizing the reductive activation mechanisms under hypoxic conditions to design and synthesize a series of nitroheterocyclic compounds and another series of anthraquinone analogs with potential of alkylation or acylation. These agents will be tested in vitro and in vivo for selective cytotoxicity towards hypoxic cells employing Chinese hamster (V-79) cells, B16 melanoma and EMT6 mammary tumor cells. The newly synthesized agents will be tested for anticancer activity in mice bearing P388 or L1210 leukemia and slower growing neoplasms such as B16 melanoma, Lewis lung, or colon carcinomas. Development of radiosensitizers has been undertaken to overcome the problem of radioresistance of hypoxic cells. An extensive structure activity relationship study is being carried out for the series of 2-nitroimidazole analogs in an attempt to reduce the neurotoxicity and increase therapeutic efficacy. New concepts leading to the design and synthesis of analogs, with potential of utilizing either the polyamine metabolism or insertion of groups that would allow depletion of non-protein thiols selectively from hypoxic cells, will be initiated. Systematic studies will be made to explore other classes of compounds, primarily the analogs of anthraquinones that may be differentially activated under acidic conditions of hypoxic environment. These agents will be tested for radiosensitization in vitro in mammalian cell systems, and in vivo in mice bearing EMT6 mammary tumor or B16 melanoma. Active agents resulting from this program will be studied for pharmacokinetics, toxicity, and biochemical mechanisms of drug action. These studies should provide the essential information to allow rational use of a radiosensitizing agent in combination with ionizing radiation for the treatment of solid tumors.
| Shalinsky, D R; McNamara, D B; Agrawal, K C (1989) Modulation of prostaglandin biosynthesis in hypoxic murine mammary adenocarcinoma cells by misonidazole. Cancer Res 49:3853-6 |
| Agrawal, K C; Rupp, W D; Rockwell, S (1986) Radiosensitization, pharmacokinetics, and toxicity of a 2-nitroimidazole nucleoside (RA-263). Radiat Res 105:227-39 |
| Gupta, R P; Larroquette, C A; Agrawal, K C et al. (1985) Potential radiosensitizing agents. 7. 4(5)-Iodo-5(4)-nitroimidazole derivatives. J Med Chem 28:987-91 |
