Biochemical, Pharmacological, and Phase I Clinical Evaluation of Pseudoisocytidine1

Pseudoisocytidine (*ICyd) is a C-nucleoside with enhanced stability and resistance to enzymatic deamination when com pared to 5-azacytidine and 1-ß-D-arabinofuranosylcytosine. Elimination kinetics in plasma using [14C]^ICyd showed a ßphase fi/2 for 14C of 2 hr and a yS-phase f,/2 of unchanged ¥ICyd of 1.5 hr. Net recovery of radioactivity in urine over 24 hr varied between 40 and 80% of the administered dose; 50 to 90% was unchanged drug and the rest was pseudouridine. Human leukemic cells in vitro deaminated *ICyd very slowly, formed appreciable quantities of Pseudoisocytidine triphosphate, and incorporated small amounts into RNA and DMA. Clinical trials were done using a daily i.v. injection for 5 con secutive days. Hematological or intestine toxicities were not seen, nor was depression of white blood cell count observed in leukemic patients. Hepatic toxicity proved to be dose limiting; this was characterized by an early phase with elevation of prothrombin time and aspartate aminotransferase. A later phase with cirrhosis was observed in two patients. Autopsy showed massive hepatic necrosis in patients dying of acute toxicity and micronodular cirrhosis in one patient dying with the chronic form.