Abstract
The anticancer effects of 9‐β‐(2′‐azido‐2′‐deoxy‐D‐arabinofuranosyl)adenine (arazide) were compared to those of 9‐β‐D‐arabinofuranosyladenine (araA) in P388 leukemia cells. Arazide was less susceptible than araA to deamination by a partially purified preparation of adenosine deaminase from P388 cells. This corresponded to significantly more cytotoxicity by arazide than by araA to P388 cells in culture; however, neither agent prolonged the survival time of mice bearing this experimental tumor. Coadministration of these agents with an inhibitor of adenosine deaminase, 2′‐deoxycoformycin (2′dCF), led to marked antineoplastic activity with arazide. Thus, daily administration of arazide (12.5–25 mg/kg per day) with 2′dCF (0.25 mg/kg per day) for 6 consecutive days to mice bearing the P388 leukemia resulted in 50% of the animals surviving for at least 50 days. In combination with 2′dCF, arazide levels higher than 25 mg/kg per day × 6 showed host toxicity as expressed by major loss in body weight and by decreased survival times of leukemia‐bearing mice. AraA plus 2′dCF in the same regimen produced only slight increases in survival time. [^3^H]‐Thymidine incorporation into DNA of P388 cells was inhibited by more than 90% following administration of a therapeutic dose of arazide and 2′dCF to leukemia‐bearing mice, and inhibition of the formation of DNA persisted for at least 24 h. Under the same experimental conditions, araA and 2′dCF caused less inhibition of DNA biosynthesis and more rapid recovery occurred. Neither arazide nor araA caused inhibition of incorporation of radioactive uridine or leucine into acid‐insoluble material. The results indicate that arazide, which is considerably more water‐soluble than araA, is also superior to araA as an antineoplastic agent when employed in combination with 2′dCF on a once‐a‐day schedule × 6, and suggest that this action is the result of potent and long‐lasting inhibition of DNA synthesis.