Arabinosyl-5-azacytosine: A novel nucleoside entering clinical trials

Jean L. Grem, D. Dale Shoemaker, Daniel F. Hoth, Susan A. King, Jacqueline Plowman, Daniel Zaharko, Charles K. Grieshaber, Steadman D. Harrison, James C. Cradock, Brian Leyland-Jones

Research output: Contribution to journalReview articlepeer-review

22 Scopus citations


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. Preclinial 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.

Original languageEnglish (US)
Pages (from-to)315-328
Number of pages14
JournalInvestigational New Drugs
Issue number4
StatePublished - Dec 1987
Externally publishedYes


  • 5-azacytidine
  • arabinosyl-5-azacytosine
  • cytosine arabinoside
  • deoxycytidine kinase

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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