Research Project
2645331
DESCRIPTION: There is an urgent need for new drugs to treat cancer, particularly solid tumors. Solid tumors often contain areas of hypoxia, thus creating a reducing environment. Hypoxic tumor cells are resistant to radiation and to many antineoplastic drugs. The overall objective of this proposal is to examine novel small molecules which are selectively activated to alkylating agents under hypoxic conditions and determine their potential as anticancer agents with preclinical studies. In this Phase I proposal the applicants intend to synthesize and develop a novel series of N-oxide prodrugs of nitrogen mustards that act through a hypoxic bystander effect so that they can be considered for full scale preclinical development, which would encompass a Phase II proposal. The Specific Aims of the proposal are as follows: (1) To synthesize bulk quantities of three of the prodrugs CHLN-O, CHL-D and MPN-O (2) To conduct in vivo antitumor studies of the compounds in SCID mice implanted with human cervical and small cell lung carcinoma xenografts and (3) To conduct pharmacokinetic studies on the derivatives in order to monitor peak times and blood levels, to aid schedule development. These studies will establish whether in vitro cytotoxic concentrations can be obtained in mice, aid in the development of optimum dosing schedules, and provide information that is essential for later Phase II toxicology and clinical studies of the compounds. PROPOSED COMMERCIAL APPLICATION: One in every five deaths in the U.S. is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. Many solid tumors are resistant to antineoplastic agents or radiation. There is a significant need to identify novel small molecule-based cancer therapies that target solid tumors. This proposal seeks to determine the feasibility of bioreductively activated Chlorambucil prodrugs for future use as drugs in the treatment of human cervical and small cell lung cancers.
