However, animals that received combination therapy showed a sig nificant reduction from baseline in body weight. The differential effects of motesanib and cisplatin on body weights in the NCI H358 and NCI H1650 models suggests that the mechan ism of body weight loss observed in the NCI H1650 model is not a general phenomenon related sellckchem to the com bination of motesanib and cisplatin. Efforts to under stand this differential activity are being explored. Effect of motesanib in combination with docetaxel on human NSCLC tumor growth Experiments parallel to those described above were per formed for motesanib and docetaxel, another standard Inhibitors,Modulators,Libraries of care chemotherapy in the treatment of NSCLC, using the A549 and Calu 6 tumor xenograft models.
To allow for the observation of additive activity, suboptimal Inhibitors,Modulators,Libraries doses of motesanib were used in some models based on previ ous dose response data. As Inhibitors,Modulators,Libraries seen with cisplatin, the anti tumor activity of the combined treatment modality was greater than Inhibitors,Modulators,Libraries that for either agent alone. In mice bearing A549 tumors, treatment with motesanib combined with docetaxel resulted in significantly greater inhibition of tumor growth than either agent alone. In this experiment, both monotherapy and combination regimens had no adverse effect on the body weight of the animals. Additive antitumor efficacy was also observed in the Calu 6 xenograft model. In mice bearing Calu 6 tumors, motesanib or docetaxel alone significantly inhibited tumor growth, and that ef fect was even greater when both agents were combined.
However, the combination of motesanib and docetaxel in the Calu 6 model was associated with a sig nificant decrease from baseline in mean body weight. To better understand the enhanced antitumor efficacy in vivo, we performed a separate set of experiments to test whether treatment Inhibitors,Modulators,Libraries with motesanib plus chemother apy had a direct effect on the proliferation of the differ ent NSCLC cell lines in vitro. There was no difference in cell viability between cisplatin or docetaxel single agent and motesanib/chemotherapy combination treatment. Results from a representative experiment with cisplatin and motesanib using Calu 6 cells are shown in Figure 5. We also investigated the possibility that the measured treatment effect of motesanib plus chemotherapy on the various tumor xenograft models was the result of changes in the plasma exposure of the respective agents.
No consistent variations in the pharmacokinetics of motesanib or either of the chemotherapy agents when administered in combination were noted in the NSCLC models tested here. This is in line with earlier experiments using xenograft models of other tumor types, reporting no significant changes in the pharmacokinetics of motesanib this research and docetaxel when administered alone or in combination.