1、CPEC induces erythroid differentiation of human myeloid leukemia K562 cells through CTP depletion and p38 MAP kinase
M Huang 1, Y Wang, M Collins, L M Graves

Abstract Cyclopentenyl cytosine (CPEC) is a carbocyclic cytidine analog inhibitor of CTP synthetase and experimental drug for combination chemotherapy. CPEC treatment (50 nM) depleted intracellular CTP and induced a specific S-phase arrest and erythroid differentiation of human erythroleukemia K562 cells. The equilibrative nucleoside transporters (ENT1, 2) facilitated uptake of CPEC into K562 cells as evidenced by both NBMPR and dipyridamole inhibition of CPEC-mediated CTP depletion and erythroid differentiation. Incubation with the pyridinylimidazole p38 MAPK inhibitors, SB203580 or SB220025, suppressed both the CPEC-induced cell cycle arrest and differentiation of K562 cells. SB203580 also prevented the cell cycle arrest and erythroid differentiation of K562 cells induced by Leflunomide (LEF), a non-nucleoside inhibitor of the de novo pyrimidine pathway, without affecting LEF-induced depletion of pyrimidine pools. Finally, selective knockdown of p38 MAPK by using Smart Pooltrade mark siRNA to p38 MAPK significantly decreased the CPEC-induced differentiation of K562 cells. These results suggest that endogenous activity of p38 MAP kinases may be required for committing K562 cells to cell cycle arrest and erythroid differentiation under conditions of CTP depletion.

2、Broad-spectrum antiviral activity of carbodine, the carbocyclic analogue of cytidine
E De Clercq 1, R Bernaerts, Y F Shealy, J A Montgomery

Abstract Carbocyclic cytidine (C-Cyd) is a broad-spectrum antiviral agent active against DNA viruses [pox (vaccinia)], (+)RNA viruses [toga (Sindbis, Semliki forest), corona], (-)RNA viruses [orthomyxo (influenza), paramyxo (parainfluenza, measles), rhabdo (vesicular stomatitis)] and (+/-)RNA viruses (reo). The target enzyme of C-Cyd is supposed to be CTP synthetase that converts UTP to CTP. In keeping with this assumption are the observations that (i) C-Cyd effects a dose-dependent inhibition of RNA synthesis in both virus-infected and uninfected cells, and (ii) exogenous addition of either Urd or Cyd reverses both the antiviral and cytocidal activity of C-Cyd, whereas addition of dThd or dCyd fails to do so. The selectivity of C-Cyd against Sindbis, vesicular stomatitis and reo virus is markedly increased when C-Cyd is combined with Cyd (10 micrograms/mL). This combination may therefore be worth pursuing as a chemotherapeutic modality for the treatment of virus infections.