The overall objected is to develop an easy controlled method of delivery for anticancer nucleoside drugs [cytarabine (araC); cladribine] in their polymeric form as oligonucleotides. The monomer drugs, currently are delivered slowly through continuous infusion in a hospital to avoid doses-related toxicities. They are phosphorytlated in the cytoplasm to the monophosphate the active metabolite. We have shown that poly araC, an oligonucleotide prodrug is degraded by nucleases to cytarabine monophosphate [araCMP] and that chimeric oligonucleotides [the prodrug] containing cytarabine and 2'O-alkyl nucleoside "speed bumps" degrade slower. Also, poly-araC, when transfected into HL-60 cells was degraded to araCMP and caused cell death. The specific aim in Phase I is to prepare various chimeric prodrug oligonucleotides with araC and 2'OMe-araU and study the rates of degradation in vitro and in HL6O and araC-resistant HL-60 cells. We expect to show that the araC-resistant cells are susceptible to araCMP, the metabolite from our prodrug oligonucleotides. We intend to show that the degradation is dependent upon 2'OMe-araU, the "speed bump nucleoside" used and that will be indicative of a controlled release version of these drugs. In Phase ll, the pharmacology, toxicology and efficacy of these oligonucleotide prodrugs in animals will be studied. PROPOSED COMMERCIAL APPLICATION: The proposed anticancer nucleoside prodrugs will localize inside the cytoplasm and in a controlled or timed release manner, degrade directly to the active metabolite {nucleoside monophosphate} in therapeutically relevant concentrations and thus reduce the cost of therapy by reducing the dose and the toxicity-related risks.
Thesaurus Terms: antineoplastic, cytosine arabinoside, drug design /synthesis /production, oligonucleotide, prodrug drug delivery system, nucleoside, phosphorus compound, slow release drug tissue /cell culture
