Xenograft models mouse

Pharmacokinetic data reported thus far show dose-proportional exposure with a short half-life of ca. 2 h. Exposure in patients receiving 250 mg/day of CP-724714 reportedly exceeds the plasma levels required for efficacy in precHnical tiunor xenograft models (50 to 60% TGI). However, robust efficacy (stasis or minor regression) in mouse models was only achieved at doses resulting in plasma exposures 40% higher than those observed in humans. From a kinetic standpoint, it appears that within 3 h, plasma concentrations in hiunans of CP-724714 fall below the levels required for pErbB knockdown in mouse models. This analysis, of course, neglects free fraction differences that may exist between species and the differential levels of active metabohtes. Enrollment in this trial continues at the 250 mg/tid dosing level. 

Sorafenib has demonstrated significant antitumor activity against a range of mouse xenograft models from breast, colon, and lung carcinomas that contain either Ras or B-Raf mutations [105]. MDA-MB-231 is the most sensitive... 

Table 9 PK/PD relationships of PD0325901 in mouse xenograft models [123]...

In addition to the original report on the activity of BMS-354825 in a SCID mouse model using a Bcr-Abl transformed cell line, other in vivo studies were also carried out. In a K562 xenograft model of CML, tumors were allowed to grow to about 300 mg [ 130]. BMS-354825 was then dosed orally once a day at 5 and 50 mg/kg, for two weeks with a dosing regime of five days on and two... 

Richmond A, Su Y (2008) Mouse xenograft models vs GEM models for human cancer therapeutics. Dis Model Mech 1 78-82... 

Futami K, Kiunagai E, Makino H et al (2008) Anticancer activity of RecQLl helicase siRNA in mouse xenograft models. Cancer Sci 99 1227-1236... 

Pimm, M. V., Durrant, L. G., and Baldwin, R. W. Influence of circulating antigen on the biodistribution and tumor localization of radiolabelled monoclonal antibody in a human tumor Nude mouse xenograft model. Eur. J. Cancer. Clin. Oncol. 25 1325-1332, 1989. 

In parallel to these studies, carbamate compounds 1 and 11-14 were assessed for their antitumor efficacy in mouse cancer xenograft models.15 When implanted human colon cancer CXF280 xenografts were grown within mice for fourteen days, doses of test compounds were administered orally. After a three-week regimen, excised tumor volumes were measured and the percent inhibition of tumor growth was calculated. From this investigation, capecitabine (1) was found to be the most effective treatment, and was furthermore found not to cause intestinal toxicity.16 All of these preclinical observations contributed to the selection of capecitabine as a candidate for further development. 

Additional results indicated that pazopanib (1) sensitized tumor cells bound to endothelial cells to DNA-damaging agents, such as melphalan. Moreover, pazopanib (1) exerted antiangiogenic and antitumor effects in vivo in a mouse multiple myeloma xenograft model. 

No rodent bioassay Tumor promotion potential was evaluated by first identifying human tumor cell lines that bind natalizumab in vitro Tumor promotion potential was then evaluated by assessing tumor growth in athymic nude mice after tumor transplantation (sc) followed by treatment with natializumab. Natalizumab did not show any tumor promoting potential on two oc4 expression tumors (leukemia, melanoma) in a nude mouse xenograft model Not genotoxic (Ames, in vitro chromosomal aberrations in human PBLs)... 

Telomerase activity can also be inhibited by the direct binding of small non-nucleosidic synthetic compounds to the hTERT reverse transcriptase component of telomerase. Schnapp and coworkers have recently reported the first mixed-type noncompetitive (70) catalytic telomerase inhibitor, (2-((E)-3-naphtalen-2-yl-but-2-enoylamino)-benzoic acid) (BIBR1532), which causes telomere shortening and senescence characteristics in various types of cancer cells in vitro and in vivo in mouse xenograft models at nanomolar concentrations (71). 

---