Inhibition of viral reverse transcriptase and leukemogenesis by modified nucleic acids

Inhibition of DNA polymerase from oncorna viruses by a new class of macromolecular inhibitors is reported. The macromolecule, designated as mercaptopolycytidylic acid (MPC), is a chemically modified polycytidylic acid containing 5-SH cytidylic bases in the polymerase. Partially thiolated polycytidylic acids (MPC I-III, containing 1.7%, 3.5%, and 8.6% 5-mercaptocytidylate units, respectively) inhibited the DNA-polymerase of Friend leukemia virus (FVL) in the endogenic reaction as well as in the presence of poly rA-(dT)14 or poly (dA-dT) templates; the inhibitory activities were directly related to the percent of tholation. In a bacterial DNA polymerase (E coli-K12 with denatured calf thymus DNA as template) MPCI-III showed no activity. Biological experiments showed that MPC III inhibits the leukemogenic potential of cell-free spleen extracts from FVL-infected mice to about 60%, measured on the basis of spleen weight. The enzymatic and animal experiments have led us to carry out preliminary clinical trials in some cases of Children leukemia. These cases, resistent to the known therapeutic regimes (combination chemotherapy), responded well when treated with MPC along, or in combination with poly I. The experiments indicate that the development of modified polynucleotids with structural similarities to functional templates may be of potential use in the future chemotherapy of leukemia.