Effect of MI-773 dosing on long-term efficacy.

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Effect of MI-773 dosing on long-term efficacy. Effect of MI-773 dosing on long-term efficacy. UM-PDX-HACC-5 tumors were transplanted in immunodeficient mice. When tumors reached 200 mm3, animals were randomly allocated into five different treatment regimens as follows: 5 mg/kg saline (vehicle control), 200 mg/kg MI-773 (weekly), 5 mg/kg cisplatin, weekly doses of MI-773 (200 mg/kg) combined with 5 mg/kg cisplatin, or daily doses of MI-773 (28.5 mg/kg) combined with 5 mg/kg cisplatin. A, Graph depicting tumor volume during treatment (tx) and follow-up (43 days) periods. Weekly regimens of MI-773 combined with cisplatin reduced tumors in size and prevented tumor regrowth compared with the other experimental groups or vehicle control. B, Graph depicting mouse weight during the experimental period. Data were normalized against pretreatment weight. C, Graph depicting a linear regression model using repeated measures for each tumor over time. Weekly regimens of MI-773 combined with cisplatin significantly decrease the tumor growth rate when compared with daily regimens of MI-773 + cisplatin or single-drug groups (P < 0.001). D, Kaplan–Meier analysis was done using a 2-fold increase in the tumor volume as a criterion for failure as compared with pretreatment volume. MI-773, cisplatin, or daily MI-773 combined with cisplatin extended time to failure significantly as compared with vehicle control (P < 0.05). Graph is depicting the statistical difference between daily and weekly regimens of MI-773 in combination with cisplatin (P = 0.0042). E, Graph depicting the volume of each individual xenograft tumor at the 10th posttreatment day. Different lowercase letters (a, b, and c) indicate statistical difference (P < 0.05). F, Western blot analysis for p53, MDM2, p21, BAX, PUMA, and Bcl-2 in UM-PDX-HACC-5 tumors treated with either MI-773 or cisplatin as single agents, weekly or daily regimens of MI-773 combined with cisplatin, or vehicle control. Tumors were harvested 43 days after the last administration of drugs. Felipe Nör et al. Clin Cancer Res 2017;23:1036-1048 ©2017 by American Association for Cancer Research