Figure 3

Anti-tumor efficacy of P7170 correlated with tumor pharmacokinetic and pharmacodynamic parameters. (A) Tumor volume (mm³) of H460 xenografts in SCID mice was measured in P7170 treatment groups twice weekly. (B) For pharmacodynamic studies, P7170 was administered into tumor bearing mice once daily consecutively for 3 days. Plasma and tumors samples were collected at 1, 4, 8, 24 h post-P7170-last dose (minimum 3 mice per time point) for estimating P7170 concentrations by LC-MS/MS. P7170 concentrations for each dose (1, 5, 10, or 20 mg/kg) were calculated based on the AUC (area under curve) constructed using concentrations at 1, 4, 8, 24 h post-P7170-last dose. Statistical significance: *p < 0.05 (C) Representative protein western blots showing response to the treatment in the experiment (B). (D) In the same experiment as in (B), part of tumor tissues was processed for western blotting analyses of proteins using specific antibodies; protein band intensities were normalized to respective loading controls. The band intensities of pS6 were plotted against the absolute plasma or tumor P7170 concentrations. The correlations of pS6 (S235/236) levels to plasma or tumor P7170 concentrations were performed using the non-compartmental analysis tool of WinNonlin Professional version 6.1: Predicted curve represents the trend in protein level derived from each tumors sample (closed circles) with respect to tumor concentrations of P7170.