POTENTIATION OF 2',3'-DIDEOXYCYTIDINE (DDC) BY HYDROXYUREA AND THYMIDINE ON THE MOLONEY MURINE LEUKEMIA-VIRUS (MOMLV) EARLY REPLICATIVE STEPS

Combinations of ddC with either the ribonucleotide reductase inhibitor hydroxyurea (HU) or with the natural nucleoside thymidine have been investigated on the cycle of a defective (psi neo) Moloney Leukemia Virus (MoMLV) using 3T3 fibroblasts as host cells. In this experimental model, ddC displayed very poor antiviral action which was obvious given an IC50 value close to 100 muM, i.e. an efficiency about thirty thousand fold lower than that of AZT. Both HU and thymidine alone resulted in significant inhibition of MoMLV replication with IC50 values of 40 muM and 100 muM respectively. The combination of ddC with 50 muM HU lowered the IC50 of ddC by a factor of 10. A similar but more pronounced effect was obtained by combining ddC and 100 muM thymidine, which decreases the IC50 value of ddC by a factor of 50. Combining 40 muM ddC and 100 muM thymidine resulted in the quite complete inhibition of viral replication. These results show that in cell types with strongly restricted ddC action, combination treatment with compounds known to ultimately decrease dCTP biosynthesis leads to the restoration of efficient antiviral activity.