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Studies on the Mode of Action of 2,2'-Anhydro-1-ß-D-arabinofuranosylcytosine¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York 14203

2,2'-Anhydro-1-ß-D-arabinofuranosylcytosine (anhydroara-C) is a more potent and less toxic antineoplastic agent than is 1-ß-D-arabinofuranosylcytosine (ara-C). In order to explain this therapeutic superiority, studies were undertaken on the mode of action of the anhydronucleoside. To facilitate these studies, anhydro-ara-C-2-¹⁴C was synthesized.

As determined with cell-free extracts of Escherichia coli, Ehrlich ascites carcinoma, and mouse leukemia L1210 cells, anhydro-ara-C is neither a substrate nor an inhibitor of the enzymes that catalyze the deamination and phosphorylation of ara-C or of 2'-deoxycytidine. Enzymatic hydrolysis of anhydro-ara-C to ara-C was not observable in these extracts or in mouse plasma, whereas nonenzymatic ring opening of anhydro-ara-C occurred. The extent of hydrolysis is pH dependent and, after 1 hr at 37°, amounts to approximately 1% at pH 6.5 and approximately 70% at pH 9.0. Uptake studies with Ehrlich ascites carcinoma cells in vitro indicated that the cell membrane presents a barrier to the entry of anhydro-ara-C into the cells. While ara-C was taken up rapidly by the Ehrlich ascites carcinoma cells during the first 5 min of incubation, only a very small amount of label derived from anhydro-ara-C-2-¹⁴C entered the intracellular space. The amount of label found in the cells corresponded approximately to the amount of anhydro-ara-C hydrolyzed to ara-C during the incubation period. A comparison of the growth response of L1210 cells, incubated at 37° in the presence of either ara-C or anhydro-ara-C, showed that the growth-inhibitory effect of ara-C commenced earlier than did that of anhydro-ara-C, and that the anhydronucleoside interrupted growth in a stepwise manner, possibly reflecting its slow hydrolysis to ara-C.

An ara-C resistant, 2'-deoxycytidine kinase-deficient subline of L1210 carried in mice was found to be crossresistant to anhydro-ara-C. Taken together, these observations suggest that anhydro-ara-C is a depot form of ara-C.

¹ This study was aided by Grant CA-12585 from the National Cancer Institute, USPHS.

Received 12/27/73. Accepted 3/ 7/73.