| AG-014699 is a potent inhibitor of Poly (ADP-ribose) polymerase (PARP) with Ki values of 1.4 and 0.17 nM for PARP-1 and PARP-2, respectively. In all human cell lines (MCF7, MDA-MB-231, OSEC1, OSEC2, HCC1937-BRCA1 and AA8) and both Chinese hamster ovary cell lines, a 30-minute exposure to 10 µM AG014699 causes greater than 94% inhibition of PARP activity, compared with untreated controls. The mean lethal concentration 50 (LC50) values of AG014699 for the homologous recombination DNA repair (HRR) functional cell lines are ranging from 20.2 µM to 50.7 µM. The mean LC50 values of AG014699 for the homologous recombination DNA repair (HRR) mutated cell lines are ranging from 1.3 µM to 5.5 µM. AG014699 is more cytotoxic to cell lines with mutations in breast cancer susceptibility gene 1/2 (BRCA1/2) or x-ray cross-complementing group 3 (XRCC3) than to those with functional HRR. BRCA1-defective HCC1937 cells (mean GI50 = 10.51 µM) are more sensitive to AG014699 than HCC1937-BRCA1 cells (mean GI50 = 16.65 µM) and BRCA1 heterozygous MDA-MB-231 cells (mean GI50 = 16.49 µM).[1] Besides, in permeabilised D283Med cells, AG-014699 (0.1, 0.4 and 1 µM) inhibits PARP-1 activity by 81.1, 96.8 and 97.1%, respectively.[2] At concentrations of 0.1, 0.4, and 1 µM, AG014699 inhibits PARP-1 activity by 92%, 98%, and 98% in NB-1691 cells and by 83%, 97%, and 100% in SH-SY-5Y cells, respectively. AG014699 (0.4 µM) significantly potentiates growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in neuroblastoma cell lines. In two independent in vivo models (NB1691and SHSY5Y xenografts), co-administration of AG014699 (1 mg/kg) and temozolomide enhances growth delay of temozolomide, and results in complete and sustained tumor regression in the majority of cases. Furthermore, in CD-1 nude mice bearing NB-1691 xenografts, AG014699 (1 mg/kg) metabolites distributes rapidly into the plasma (Cmax, 1.2-1.9 nM at 30 minutes) and accumulates in xenograft tissues (Cmax, 1-2 µM at 120 minutes).[3] Furthermore, in SW620 tumor xenografts model, AG014699 (1 mg/kg) improves tumor perfusion comparably with the control agents nicotinamide and AG14361.[4] |
