ABSTRACT
ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a pharmacodynamic marker, ADP ribose polymers (pADPr), after ABT 888 treatment. ABT-888 enhanced TMZ antitumor activity, in a dose-proportional manner with no observed toxicity (44-75% tumor growth inhibition vs. TMZ monotherapy), but did not show single agent activity. Extended ABT-888 dosing schedules showed no advantage compared to simultaneous TMZ administration. Efficacy correlated with plasma/tumor drug concentrations. Intratumor drug levels correlated with a dose-proportional/time-dependent reduction in pADPr. Potentiation of TMZ activity by ABT-888 correlated with drug levels and inhibition of PARP activity in vivo. ABT-888 is in Phase 1 trials using a validated ELISA based on the assay developed here to assess pharmacological effect.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzimidazoles/pharmacology , Dacarbazine/analogs & derivatives , Melanoma, Experimental/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Benzimidazoles/administration & dosage , Benzimidazoles/pharmacokinetics , Cell Line, Tumor , Dacarbazine/administration & dosage , Dacarbazine/pharmacokinetics , Dacarbazine/pharmacology , Drug Administration Schedule , Drug Synergism , Melanoma, Experimental/enzymology , Melanoma, Experimental/metabolism , Mice , Poly Adenosine Diphosphate Ribose/metabolism , Poly(ADP-ribose) Polymerases/metabolism , TemozolomideABSTRACT
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.
