Antitumor effect of the nucleoside analogs 2-chlorodeoxyadenosine and 2',2'-difluorodeoxycytidine on human hepatoma...

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 hepatocellular carcinoma are still very poor. The nucleoside analogs 2-chlorodeoxyadenosine (Cladribine, 2-CdA) and 2',2'-difluorodeoxycytidine (Gemcitabine, dFdC) have shown potent cytotoxic effects on various human tumor cell lines in vitro and marked therapeutic efficacy in the treatment of lymphoproliferative disorders and several solid tumors in vivo. In the present study we evaluated the antitumor effect of 2-CdA and dFdC on human hepatoma HepG2 cells.

HepG2 cells were grown in the absence and presence of increasing concentrations of 2-CdA and dFdC. Antitumor activity was assessed by inhibition of cell growth, evaluated by counting cell numbers in a hemocytometer and by 3H-thymidine uptake, and by reduction of cell viability as determined by exclusion of 0.1% trypan blue. For rescue experiments, the natural pyrimidine deoxycytidine (dCyd) was added simultaneously or delayed.

A strong 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 drugs achieved their half-maximal antitumor activity after 31 h. With respect to dFdC, fractionated daily administrations showed a distinctly greater antitumor activity than a single transient administration. The cytotoxic effects of 2-CdA and dFdC were completely reversed by simultaneous addition of dCyd.

In this paper we show strong antitumor effects of the nucleoside analogs 2-CdA and dFdC on the human hepatoma cell line HepG2. These findings suggest that both compounds, but in particular dFdC, are promising substances for further evaluations in the treatment of hepatocellular carcinoma.