Importance of timing and length of administration of angiogenesis inhibitor TNP-470 in the treatment of K12/TRb colorectal hepatic metastases in BD-IX rats

Background: The timing and length of administration of angiogenesis inhibitor TNP-470 was altered to evaluate the effect on disease progression in a rat model of colorectal hepatic metastases. Methods: Pair-fed BD-IX rats, injected intrasplenically with rat colon adenocarcinoma K12/TRb cell, at day 0, were randomized to receive subcutaneous injections of either placebo or 15 mg/hg TNP-470 on alternate days: for 2 weeks beginning 24 hours after tumor inoculation ('Early'), for 4 weeks beginning 24 hours after tumor inoculation ('Prolonged'), or for 2 weeks beginning at day 15 after macroscopic tumor nodules were confirmed ('Delayed'). Response to treatment was evaluated by counting tumor nodules on the surface of the liver at laparotomy on day 14 and 28 after tumor inoculation. The animals were followed for survival and cause of death. Results: Maximal suppression of hepatic metastases at day 28 required 4-week rather than 2-week TNP-470 administration. Prolonged TNP-470 administration resulted in significantly fewer hepatic metastases at day 28 compared to control (P < .05). Early and prolonged TNP-470 improved survival (Wilcoxon test, P < .05) compared with delayed TNP-470 and placebo. Delayed TNP-470 administration did not increase survival or significantly diminish the number of metastases at day 28 compared with placebo. Conclusions: These data suggest that prolonged adjuvant antiangiogenic therapy may suppress colorectal hepatic micrometastases.