Renal Cell Carcinoma – Xenotransplantation into Immunosuppressed Mice

Kopper, László; Magyarosy, Edina; Nagy, Péter; Lapis, K.; Számel, I.; Eckhardt, S.; Csata, S; Wabrosch, G; Répássy, D

doi:10.1159/000225784

Cited by 7 publications

(4 citation statements)

References 6 publications

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“…83 PDTX models of RCC have been used for decades and may provide several advantages over cell line xenografts. 80–85 RCC cells continuously cultured in vitro are known to acquire many genetic alterations not found in the original tumour. 86 In addition, the limited number of RCC cell lines available means that they lack the heterogeneity that characterizes kidney cancer in the human population.…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

“…18,87 Several studies have demonstrated that RCC PDTX models are similar to parental tumours as assessed by histology, karyotype, DNA-ploidy, and molecular cytogenetic analyses. 80–85,88 Grisanzio et al 80 have also created orthotopic PDTX that exhibit high levels of histological, immunophenotypical and genetic concordance between the PDTX and the corresponding primary tumour. Another advantage of an RCC PDTX model is the ability to evaluate tumour angiogenesis, and studies have demonstrated that the vasculature of RCC PDTX are predominantly comprised of human endothelial cells, up to 35 days after implantation.…”

Section: Renal Cell Carcinomamentioning

confidence: 99%

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Patient-derived tumour xenografts as models for oncology drug development

et al. 2012

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Progress in oncology drug development has been hampered by a lack of preclinical models that reliably predict clinical activity of novel compounds in cancer patients. In an effort to address these shortcomings, there has been a recent increase in the use of patient-derived tumour xenografts (PDTX) engrafted into immune-compromised rodents such as athymic nude or NOD/SCID mice for preclinical modelling. Numerous tumour-specific PDTX models have been established and, importantly, they are biologically stable when passaged in mice in terms of global gene-expression patterns, mutational status, metastatic potential, drug responsiveness and tumour architecture. These characteristics might provide significant improvements over standard cell-line xenograft models. This Review will discuss specific PDTX disease examples illustrating an overview of the opportunities and limitations of these models in cancer drug development, and describe concepts regarding predictive biomarker development and future applications.

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Section: Renal Cell Carcinomamentioning

confidence: 99%

Section: Renal Cell Carcinomamentioning

confidence: 99%

Patient-derived tumour xenografts as models for oncology drug development

et al. 2012

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“…Second, RCC is seldom treated with chemotherapy, and thus, the molecular genetics and behavior of the tumor is unlikely to be affected by previous exposure to DNA damaging agents. Third, RCCs implanted in mice preserve the histology and karyotype of patient tumors (10)(11)(12)(13)(14)(15)(16). Fourth, the implantation of tumors heterotopically in mice may affect tumor biology (17)(18)(19), but the site for orthotopic implantation of RCC, under the kidney capsule, is a privileged site for tumor growth (4).…”

Section: Introductionmentioning

confidence: 99%

A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma

et al. 2012

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Most anticancer drugs entering clinical trials fail to achieve approval from the US FDA. Drug development is hampered by the lack of preclinical models with therapeutic predictive value. Herein, we report the development and validation of a tumorgraft model of renal cell carcinoma (RCC) and its application to the evaluation of an experimental drug. Tumor samples from 94 patients were implanted in the kidney of mice without additives or disaggregation. Tumors from 35 patients formed tumorgrafts, and 16 stable lines were established. Samples from metastatic sites engrafted at high frequency, and stable engraftment of primary tumors in mice correlated with decreased patient survival suggesting that tumor growth in mice may reveal the acquisition by the tumor of an ability to thrive at distant sites and metastasize. Tumorgrafts retained the histology, gene expression, DNA copy number alterations, and over 90% of the protein-coding gene mutations of the corresponding tumors. As determined by the induction of hypercalcemia in tumorgraft-bearing mice, tumorgrafts were able to act on the host causing paraneoplastic syndromes. In studies simulating drug exposures in patients, RCC tumorgraft growth was inhibited by sunitinib and sirolimus (into which temsirolimus is converted in humans), but not by erlotinib, which was used as a control. Dovitinib, a drug in clinical development, showed greater activity than sunitinib and sirolimus. The routine incorporation of models recapitulating the molecular genetics and drug sensitivities of human tumors into preclinical programs has the potential to improve oncology drug development.

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“…The sensitivity of this embryonal carcinoma line to chemotherapy was much higher than that of other tumor types (colorectal carcinoma, renal cell car cinoma [6,11]). Similar conclusions were drawn by Steel et al [8] who compared the chemotherapeutic response of 6 tumor types (testicular teratoma, small cell and non-small cell lung carcinoma, breast car cinoma, colorectal carcinoma, melanoma) growing as xenografts in immunosuppressed mice.…”

Section: Lapis Kopper Bodrogi Sugar Lapis Eckhardtmentioning

confidence: 72%

Characteristics and Chemotherapeutic Sensitivity of a Human Testicular Cancer Grown in Artificially Immunosuppressed Mice

et al. 1985

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Seven human testicular tumors were transplanted into artificially immunosuppressed mice. Two of them grew progressively (TT2 and TT6) and a serially transplantable line was developed from TT2. The xenografts maintained only the embryonal carcinoma components of originally mixed (embryonal cell carcinoma and choriocarcinoma) donor tumor. Although the histology did not change remarkably with passages, the xenografts lost their capacity to express human choriogonadotropin and α-fetoprotein. The latency period shortened, the growth rate remained similar with subsequent transplantations. The tumor cells of the TT2 line presented the human character according to chromosome analysis and were built up of two subsets of cells with a different DNA index estimated by flow cytometry. The embryonal cell carcinoma line was highly sensitive to CY and cisDDP. PVB combination was also effective, although the tumor growth inhibition proved to be only temporary.

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Renal Cell Carcinoma – Xenotransplantation into Immunosuppressed Mice

Cited by 7 publications

References 6 publications

Patient-derived tumour xenografts as models for oncology drug development

Patient-derived tumour xenografts as models for oncology drug development

A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma

Characteristics and Chemotherapeutic Sensitivity of a Human Testicular Cancer Grown in Artificially Immunosuppressed Mice

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