Immunosuppressive, antiviral and antitumor activities of cytarabine derivatives

Abstract

Although cytarabine (cytosine arabinoside, ara-cytidine, Cytosar) is a potent immunosuppressant, antiviral and antitumor agent in animals and man, maximum inhibitory effects require the use of complex injection schedules. Previous reports have shown that good immunosuppressive and antitumor activities were attained with simple injection schedules using the 5′-adamantoate derivative. The current results show that a variety of 5′-acylates were equally as active as the 5′-adamantoate in suppressing immune responses in rodents (hemagglutinin formation in mice and hamsters, skin graft rejection in rats), and as antitumor agents in mice (L1210 leukemia). Similar results were attained in protecting mice from the lethal effects of intracranial herpes simplex infection, and in inhibiting DNA synthesis in phytohemagglutinin-stimulated human lymphocytes. The hypothesis for the enhanced potency of these newer derivatives was as follows: After injection of these insoluble derivatives, there is a finite time required for dispersion and solubilization. The freely circulating derivatives are resistant to deamination (and inactivation). After enzymatic hydrolysis to the free acid and cytarabine, the latter is then free to exert its inhibitory activities. The net effect is the maintenance of relatively low levels of cytarabine for long periods of time.