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 i n 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.
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.
