High impact information on CI 1000

• Comparative in vitro and in vivo activities of two 9-deazaguanine analog inhibitors of purine nucleoside phosphorylase, CI-972 and PD 141955 [1].
• PD 141955 induced accumulation of dGTP in GdR-treated MOLT-4 and CEM cells at log-lower concentrations than were required of CI-972, and the magnitude of dGTP accumulation in PD 141955-treated T cell cultures was markedly greater (e.g. 366 vs 100 pmol/10(6) CEM cells at 10 microM) [1].
• The following findings support the conclusion that PNP reduces AsV to AsIII, using AsV instead of phosphate in the reaction above: (1) Specific PNP inhibitors (CI-1000, BCX-1777) at a concentration of 1 microM completely inhibited cytosolic AsV reductase activity [2].
• Lastly, a pan caspase inhibitor (Z-D-DCB) and 2'-deoxycytidine (dCyd), which is known to prevent dGTP accumulation following PNP inhibition, were able to prevent cell death and all indicators of caspase-3-like activity in MOLT-4 cells co-treated with dGuo and CI-1000 [3].
• Plasma CI-1000 levels were higher in females than in males at all doses except 15 mg/kg; Cmax and AUC values were largely dose proportional in both sexes [4].

Biological context of CI 1000

• Pharmacokinetics/pharmacodynamics of CI-1000, a purine nucleoside phosphorylase (PNP) inhibitor, in rats and monkeys [5].

Analytical, diagnostic and therapeutic context of CI 1000

• The ability of CI-1000 to retard nucleoside breakdown in blood in vitro may be a predictor of in vivo activity, and can be viewed as an early and essential biochemical consequence of PNP inhibition culminating in immunosuppression [6].

References