SBIR-STTR Award

The central objective of this project is to develop a series of new drugs that provide increased radiosensitization of hypoxic tumors and reduced toxicity to normal tissues. The newly synthesized drugs are metronidazole conjugates designed as DADM and DATM. Preliminary studies suggest that these drugs show greatly improved tumor-plasma ratios and increased drug stability. Another novel feature of these drugs is their ability to optimize the reaction range of the functional groups. Tissue culture studies in Chinese hamster ovary cells, mammary adenocarcinoma cells, and human prostate cancer cells indicate that DATM is 50 to 500 times more effective than metronidazole in sensitizing hypoxic tumor cells. Preliminary studies on tumor-bearing mice suggest that DATM is equally effective in animals. During Phase I of this project the three promising DATM compounds will be used to test toxicity and radiosensitization in mice, using the tumor regrowth assay. Also, drug pharmacokinetics in mice will be studied to evaluate drug stability, tissue distribution, tumor to plasma ratio, normal tissue toxicity, and kinetics of drug metabolism and excretion.National Cancer Institute (NCI)

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. PROPOSED COMMERCIAL APPLICATION: 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.