ANTITUMOR EFFECT OF THE NUCLEOSIDE ANALOGS 2-CHLORODEOXYADENOSINE AND2',2'-DIFLUORODEOXYCYTIDINE ON HUMAN HEPATOMA HEPG2 CELLS

Background/Aims: Hepatocellular carcinoma is one of the most malignant tumors in the world, Although a wide range of therapeutic options is available, the efficacy of these methods and the prognosis of hepatoce llular carcinoma are still very poor, The nucleoside analogs 2-chlorod eoxyadenosine (Cladribine, 2-CdA) and 2',2'-difluorodeoxycytidine (Gem citabine, dFdC) have shown potent cytotoxic effects on various human t umor cell lines in vitro and marked therapeutic efficacy in the treatm ent of lymphoproliferative disorders and several solid tumors in vivo, In the present study we evaluated the antitumor effect of 2-CdA and d FdC on human hepatoma HepG2 cells. Methods: HepG2 cells were grown in the absence and presence of increasing concentrations of 2-CdA and dFd C, Antitumor activity was assessed by inhibition of cell growth, evalu ated by counting cell numbers in a hemocytometer and by H-3-thymidine uptake, and by reduction of cell viability as determined by exclusion of 0.1% trypan blue, For rescue experiments, the natural pyrimidine de oxycytidine (dCyd) was added simultaneously or delayed. Results: A str ong antitumor activity was observed for both compounds. dFdC showed a more pronounced effect with an inhibition constant (IC50) of 3.98+/-0. 03 nM in comparison to 2-CdA with an IC50 of 16.66+/-0.40 nM. Both dru gs achieved their half-maximal antitumor activity after 31 h, With res pect to dFdC, fractionated daily administrations showed a distinctly g reater antitumor activity than a single transient administration. The cytotoxic effects of 2-CdA and dFdC were completely reversed by simult aneous addition of dCyd. Conclusion: In this paper we show strong anti tumor effects of the nucleoside analogs 2-CdA and dFdC on the human he patoma cell line HepG2. These findings suggest that both compounds, bu t in particular dFdC, are promising substances for further evaluations in the treatment of hepatocellular carcinoma.