We used a statistical approach that enabled us to first eval uate the effect of

As examples of LD chemotherapy we buy AS703026 used paclitaxel, a drug commonly used in ovarian and other cancers, while as an example of antiangiogenic ther apy we used SU5416, a tyrosine kinase inhibitor with activity against VEGF receptor 2, which has been used in the clinic in combinations, We used the ID8 and ID8 Vegf mouse models of ovarian can cer to address the above questions, ID8 cells express constitutively low levels of Vegf A, while ID8 Vegf cells were retrovirally transduced to express constitutively high levels of Vegf164 isoform. This model recapitulates closely human ovarian cancer. We have shown that ID8 Vegf tumors maintain significantly higher levels of Vegf A expression in vivo; exhibit increased angiogenesis and growth; and are associated with significantly shorter sur vival relative to ID8 tumors.<br><br> Importantly, supplier AZD1152-HQPA tumor, ascites and serum levels of Vegf A protein in animals bearing ID8 VEGF tumors were significantly higher than in animals bearing control ID8 tumors, but both were within the range described in human ovarian cancer, To analyze the interactions between tumor Vegf, LD chemotherapy and SU5416, we used a novel method of statistical mode ling that involves fitting functional linear models using weighted penalized least squares, This approach enabled us to investigate interactions between LD chemo therapy and antiangiogenic therapy through simple exper iments. We found a significant difference in tumor response depending on Vegf expression. LD chemotherapy yielded additive effects with antiangiogenic therapy only against tumors with low Vegf expression, while it exhibited antag onism to antiangiogenic therapy in tumors with high Vegf expression.<br><br> This is the first preclinical study that models interactions of LD chemotherapy with antiangiogenic therapy and tumor Vegf expression and offers important lessons for the rational design of clinical trials. Materials and methods Cell culture and reagents The development and characterization of ID8 Vegf cell line was described elsewhere AMN-107 構造 in detail, ID8 and ID8 Vegf cells were maintained in DMEM media supplemented with 10% fetal bovine serum, 100 U ml penicillin, and 100 strepto mycin in a 5% CO2 atmosphere at 37 C. Mice and treatments Six to eight week old female C57BL 6 mice were used in protocols approved by the IACUC of the University of Pennsylvania.<br><br> Mice were treated with intraperitoneal bolus injec tions of pacitaxel, SU5416 or dimethyl sulfoxide, Paclitaxel or saline alone were given i. p. on days 1 and 4 every week. This dose is approximately one fourth of maximally toler ated doses for mice and are within metro nomic range. SU5416 or DMSO alone were given i. p. on days 1, 3, and 5 every week. This dose of SU5416 and DMSO are MTD for C57BL 6 mice, as were identified by dose defining experiments in healthy 6 week old female C57BL 6 mice, Higher doses of SU5416 or DMSO resulted in significant weight loss or mortality. containing recombinant mouse Vegf164, One day after Matrigel injection, mice were treated with i. p. paclitaxel and or SU5416 or DMSO at the above doses. Paclitaxel or saline were given i. p. on days 1 and 4. SU5416 or DMSO were given on days 1, 3, and 5. Matrigel plugs were removed under anesthesia 7 days later and were snap frozen in liq uid nitrogen.