The goal of this project is to test a series of new metronidazole derivatives that combine two important biological properties: (1) increased radiosensitization of hypoxic tumors; (2) reduced toxicity to normal tissues. The drugs consist of 2-5 metro rings covalently linked via diamine or triamine linkers. When compared to free metronidazole, conjugates yield improved tumor-plasma ratios, increased drug stability, and reduced toxicity in mice. Another novel feature of metro conjugates is their ability to optimize the reaction range of the functional groups by varying the length of the linker region (3-8 carbon). In vitro experiments on Chinese hamster ovary cells, mammary adenocarcinoma cells, and human prostate cancer cells indicate that conjugates are 20-500 times more potent than free metro in radiosensitizing hypoxic cells. Studies on tumor-bearing mice show that the conjugates are also very effective in animals. During Phase II the drugs will be further tested in vitro to assess cytotoxic and radiosensitizing effects, cell cycle effects, mutation induction, and micronucleus formation. Promising compounds will be examined in mice to evaluate drug toxicity and radiosensitization in MTG-B mouse mammary tumors, human breast cancers (MCF-7, MX-1), and prostate (DU-145) cancers. In addition, drug pharmacokinetic studies will be performed to monitor drug stability, tissue distribution, tumor/plasma ratio, and the kinetics of drug metabolism and excretion.
Our newly synthesized metro conjugates (in particular diaminetetrametronidazoles) combine greatly enhanced hypoxic cell radiosensitization with reduced normal tissue toxicity in mice. If this holds true for humans, the drug would have considerable potential for clinical application.
