Arabinosyl-5-azacytosine is a new compound which has been selected by the Division of
Cancer Treatment, National Cancer Institute for clinical development as an
antineoplastic agent based on its high degree of activity against a broad range of
tumor types in preclinical studies. Therapeutic activity has been observed against murine and human
leukemias, transplantable murine solid
tumors, and human
tumor xenografts.
Arabinosyl-5-azacytosine exhibited a broader spectrum of activity against human solid
tumors than
cytosine arabinoside.
Arabinosyl-5-azacytosine is phosphorylated to the
nucleotide level by
deoxycytidine kinase. Upon further anabolism to the
triphosphate level, it can be incorporated into
DNA. The mechanism of cytotoxicity is thought to be related to inhibition of
DNA synthesis. Leukemic and solid tumor cell lines that are resistant to
cytosine arabinoside due to deletion of
deoxycytidine kinase activity are cross-resistant to
arabinosyl-5-azacytosine. Unlike
cytosine arabinoside,
arabinosyl-5-azacytosine does not readily undergo deamination. Schedule dependence has been demonstrated in mice bearing
L1210 leukemia, with superior activity seen with multiple doses administered on each treatment day compared to administration of larger but less frequently administered doses. From preliminary data in solid
tumor models, however, antitumor activity did not appear to be superior with continuous infusion compared to that observed on a bolus schedule. Preclinical toxicology studies indicated that the bone marrow and gastrointestinal tract were the main target organs. A single large dose of
arabinosyl-5-azacytosine could be tolerated by both mice and dogs. When administered as a continuous infusion, the toxicity was related to both the dose and duration of exposure, suggesting that toxicity resulted from a critical time above a threshold concentration as opposed to the total area under the concentration-time curve. Phase I clinical trials have been initiated to determine the maximum tolerated dose on a low dose continuous infusion schedule for 72 hours and also on a high dose short infusion daily times five schedule.