Biochemical and pharmacologic studies with 1-β- d-arabinofuranosylcytosine 5′-adamantoate (NSC-117614), a depot form of cytarabine

Abstract

In the treatment of L1210 leukemic mice, the antitumor activity observed with 1-β- d-arabinofuranosylcytosine 5′-adamantoate (AdO- ara-C) suggested that the agent represents a molecular depot form or sustained action form of 1-β- d-arabinofurano-sylcytosine ( ara-C, cytarabine). The results of the present study provide strong support for this hypothesis. Many biochemical similarities between ara-C and AdO- ara-C were observed, suggesting similar or identical modes of action. Cytotoxicity of both agents in cell culture could be prevented with deoxycytidine. Like ara-C, AdO- ara-C markedly inhibited DNA synthesis with little effect on RNA or protein synthesis. Cross-resistance (L1210 cells in culture) was also observed. The differences observed in vitro (e.g. lower intrinsic Cytotoxicity, lower extent of uptake by L1210 cells, slower kinetics of inhibition of DNA synthesis with the derivative) were also consistent with the hypothesis that hydrolysis of AdO- ara-C to ara-C is required for cytotoxic activity. Direct evidence for hydrolysis was obtained in studies of the metabolism in vitro of AdO- ara-C in mammalian plasma and in plasma level studies in mice. Inhibition of enzymatic hydrolysis with an esterase inhibitor (eserine sulfate) markedly reduced the Cytotoxicity of AdO- ara-C towards L1210 cells in culture. Plasma level and excretion studies indicated that i.p. administration of AdO- ara-C to mice yielded cytotoxic ara-C levels which persisted for much longer than is possible with a single dose of the parent compound itself. These data, when considered with those concerning the effects of low levels of ara-C in contact with cells in culture for long periods help to explain the unusual therapeutic effects of AdO- ara-C.