In vivo xenograft model

With the in vitro success of 6, 12, and 17 against the OVCAR-3 and MB157 cancer cell lines, an in vivo xenograft model was developed using 6 and the ovarian cancer cell line. OVCAR-3 cells were subcutaneously injected into the back of female athymic nude mice, an appropriate animal model for this type of study. After approximately six weeks, visible tumor growth was apparent, and a subcutaneous injection of 6 was made at the tumor site every third day for 10 days. The delay between injections was required due to the slow absorption of the compound. Each dose consisted of 333mgkg of 6, for an overall dose of... 

In agreement with the aberrant HDAC/HAT activity equilibrium in cancer, HDAC inhibitors have been shown to induce cell-cycle arrest, terminal differentiation and/or apoptosis in a broad spectrum of human tumor cell Unes in vitro, to inhibit angiogenesis and to exhibit in vivo antitumor activity in human xenograft models in nude mice [10-12]. Several HDAC inhibitors are in advanced stages of development and antitumor activity has been observed in hematological malignancies at doses that were well tolerated (Sect. 3). 

While no in vivo activity has been reported in an Abl-dependent CML model, AZD0530 was active in a xenograft model using Src-transformed NIH 3T3 cells and in an orthotopic model of pancreatic cancer, two Src-dependent models. The results of a Phase I trial in normal volunteers have been disclosed and AZD0530 was tolerated when administered at doses of up to 250 mg [156,157]. While it appears that the initial efficacy trial for AZD0530 will be as an anti-invasive agent for the treatment of metastatic bone disease, this compound probably also has potential for use in CML. 

Rubio-Viqueira B, Hidalgo M (2009) Direct in vivo xenograft tumor model for predicting chemotherapeutic drug response in cancer patients. Clin Pharmacol Ther 85 217-221... 

Fig. 15 T/C values for in vivo xenograft mouse models using the human cell lines PC3, CAKI-1, A431 and MCF-7 in connection with titanocenes 3 and 14...

Products that may have the potential to stimulate growth or induce proliferation or clonal expansion of cell types, in particular, transformed cells, all processes that may eventually lead to neoplasia should be evaluated with respect to receptor expression in various malignant and normal human cells that are relevant to the patient population under study [27], In such cases normal human cell lines and multiple human cancer cell lines expressing the relevant receptor, as well as primary cells derived from human tumor explants, should be used for in vitro assessment. When in vitro data demonstrate enhanced growth, further studies in relevant in vivo xenograft animal models with receptor expressing tumor cell lines may be needed. In addition incorporation of sensitive indexes of cellular proliferation in long-term repeat-dose toxicity studies may provide useful information. 

DHA-paclitaxel (Taxoprexin ) 62 (Luitpold) is being evaluated in a Phase III trial for the treatment of advanced non-small cell lung cancer in combination with carboplatin,136 as well against a variety of cancers in Phase II trials. DHA-paclitaxel 62,137 139 which is the C-2 docosahexaenoic acid (DHA) ester of paclitaxel 60, was licensed by Luitpold from Protarga in 2003. Polyunsaturated fatty acids have been reported to be taken up by tumour cells at a higher rate than normal cells and, as a consequence, a polyunsaturated fatty ester such as DHA-paclitaxel 62 may be absorbed more specifically in tumour cells. In preclinical studies, DHA-paclitaxel 62 exhibited increased activity in mice xenograft models and was more stable in vivo than paclitaxel 60. However, DHA-paclitaxel 62 may still suffer from efflux problems associated with paclitaxel 60 and docetaxel resistant tumours. 

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). 

Wolff NC, Randle DE, Egorin MJ, et al. Imatinib mesylate efficiently achieves dierapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. Clin Cancer Res... 

Measurements from the in vivo invasion assay have been shown to correlate with the metastatic properties of cancer cells in a xenograft model of breast cancer, with more metastatic cells invading 15-fold more efficiently than less metastatic cancer cells in response to an EGF gradient, correlating with their in vitro chemotactic responses to EGF (10). Transgenic models of breast cancer have also been examined, and the invasiveness of breast cancer cells to chemoattractants such as TGF-a and heregulin among others was evaluated in the polyoma Middle T model (11). 

In Vivo Efficacy of Ouabain in a Xenograft Model of Retinoblastoma. 3747... 

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). 

In vivo studies were carried on the aziridinated cyclopent[Z ]indole quinone out before it was discovered that the aziridinyl ring did not participate in DNA alkylation. The results in Fig. 7.22 for the B16 melanoma syngraft model reveal that there was substantial reduction of tumor mass at 3 mg/kg. However, toxicity (animal deaths) became apparent at 5 mg/kg. On the other hand, human lung cancer xenografts in SCID (severe combined immunodeficient) mice were reduced to 50% mass with 3x1 mg/kg doses without any animal deaths. 

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