Tumor Xenograft Models

At the in vivo assay level, the classic ip-ip (iateraperitoneal) in vivo model has been replaced as a selection criteria for advancement of new dmg candidates to clinical trial. More stringent alternative models iaclude subcutaneous or subrenal capsule implantation of tumor followed by iatravenous dmg dosiag (7) and the human tumor xenograft models ia aude mice (8). 

Needham D, Anyarambhatia G, Kong G, Dewhirst MW. A new temperature-sensitive liposome for use with mild hyperthermia characterization and testing in human tumor xenograft model. Cancer Res 2000 60 1197-1201. 

ARRY-334543 shows robust efficacy in several hiunan tumor xenograft models, including BT-474, MDA-MB-453, H1650, Calu3, and A431 [81,82]. Target inhibition in vivo or PK/PD relationships have not been reported. ARRY-334543 recently entered phase I trials no data have been reported. 

This compound is effective in tumor xenograft models when dosed orally or IV. Compoimd 42 is in safety and tolerability studies in humans. 

Of all the 4-anilino-3-quinoHnecarbonitrile dual Src/Abl inhibitors, the most extensively profiled analog is SKI-606. Pharmacokinetics showed SKI-606 to have an oral bio availability in nude mice of 18% and a half-hfe of 8.6 hours with a large volume of distribution [122]. SKI-606 was active in several colon tumor xenograft models when dosed orally at 25-150 mg/kg daily for 21 days with no weight loss or overt toxicity noted in the animals. On the basis of its pre-clinical properties, SKI-606 entered clinical trials in 2004 for the treatment of solid tumors and will soon be entering trials for the treatment of CML. 

Joschko MA, Webster LK, Groves J, et al. Enhancement of radiation-induced regrowth delay by gemcitabine in a human tumor xenograft model. Radiat Oncol Investig 1997 5(2) 62-71. 

Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995 1 1311— 1318. 

In a human tumor xenograft model, Kong et al.21 compared the antitumor effect of doxorubicin encapsulated in three types of liposome formulations, a nonthermosensitive liposome (NTSL), a traditional thermosensitive liposome (TTSL), and a low-temperature-sensitive liposome (LTSL). All three liposomes are sterically stabilized with PEG grafted on their surface. All the liposomes have a long circulation time and can accumulate selectively in tumor tissue. However, the lipid compositions of the three formulations are different. The NTSL was composed of saturated long-chain lipids such as hydrogenated soybean... 

Kong, G., Anyarambhatla, G., Petros, W.P, et al. Efficacy of liposomes and hyperthermia in a human tumor xenograft model Importance of triggered drug release. Cancer Res. 60(24) 6950-6957. 2000. 

Further modifications of the liposomal composition have led to an improved formulation of the cationic liposomes containing raf ASO (md-LErafAON). The md-LErafAON formulation exhibits superior safety and pharmacokinetic profiles and is an effective anti-tumor agent in a human prostate tumor xenograft model. 

Golas JM, Lucas J, Etienne C, Golas J, Discafani C, Sridharan L, Boghaert E, Arndt K, Ye F, Boschelli DH, Li F,Titsch C, Huselton C, Chaudhary I, Boschelli F. FSKI-606, a Src/Abl inhibitor with in vivo activity in colon tumor xenograft models. Cancer Res 2005 65 5358-64. 

Plowman J, Dykes JJ, Hollingshead MG, Simpson-Herren L, Alley MC. Human tumor xenograft models in NCI drug development. In Teicher BA, editor. Anticancer drug development guide Preclinical screening, clinical trials and approval. Totowa, NJ Humana Press 1997. p. 101-25. 

Liu M, Bryant MS, Chen J, Lee S, Yaremko B, et al. 1998. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res. 58 4947-56... 

Pedley, P. B., Dale, R., Boden, J. A., Begent, R. H Keep, P. A., and Green, A. J. (1989) The effect of second antibody clearance on the distribution and dosimetry of radiolabelled anti-CEA antibody in a human colonic tumor xenograft model. Int. J. Cancer 43, 713-718. 

Rowlinson-Busza, G., Deonarain, M. P., and Epenetos, A. A. (1996) Comparison of intact monoclonal antibody, its F(ab ) 2 and Fab fragments and recombinant single chain Fv in a human tumor xenograft model. Tumor Target. 2, 37-48. 

Altered acetylation patterns are a hallmark [9] of many primary tumor types. The best evidence for the importance of HDACs in cancer comes from studies with small molecule HDAC inhibitors, ranging from cell-based in vitro experiments to tumor xenograft models and human clinical trials. Reassuringly, despite the potential for HDAC inhibitors to affect a range of... 

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