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Tang T.C.,Molecular and Cellular Biology Research | Man S.,Molecular and Cellular Biology Research | Lee C.R.,Molecular and Cellular Biology Research | Xu P.,Molecular and Cellular Biology Research | And 2 more authors.
Neoplasia | Year: 2010

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficientmice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfectedwith the gene encoding secretable β-subunit human choriogonadotropin (β-hCG),whichwas used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicitywas observed using either single or doubletmetronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survivalwas observed using various combinations ofmetronomic chemotherapy regimens such as UFT+CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment. Copyright © 2010 Neoplasia Press, Inc. All rights reserved. Source

Francia G.,Molecular and Cellular Biology Research | Cruz-Munoz W.,Molecular and Cellular Biology Research | Man S.,Molecular and Cellular Biology Research | Xu P.,Molecular and Cellular Biology Research | Kerbel R.S.,Molecular and Cellular Biology Research
Nature Reviews Cancer | Year: 2011

An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Tang T.C.,Molecular and Cellular Biology Research | Man S.,Molecular and Cellular Biology Research | Xu P.,Molecular and Cellular Biology Research | Francia G.,Molecular and Cellular Biology Research | And 5 more authors.
Neoplasia | Year: 2010

Acquired resistance to antiangiogenic drugs, such as sorafenib, is amajor clinical problem. Westudied development of a resistance to sorafenib in new preclinical models of human hepatocellular carcinoma (HCC) along with a strategy to delay such resistance-combination with metronomic chemotherapy. Three different xenograft models were studied using human Hep3B HCC cells, which are highly responsive to sorafenib, namely, orthotopic and subcutaneous transplant in severe combined immunodeficientmice, and an orthotopic transplant in nudemice. The complementary DNA for the β-subunit of human choriogonadotropin was transfected into HCC cells, and urine levels of the protein were monitored as a surrogate of tumor burden. Extended daily treatments, sometimes interrupted by a break period of 3 to 7 days to allowrecovery fromtoxicity at sorafenib doses of 30 to 60 mg/kg, were maintained until and after evidence of tumor relapse. Initially responsive tumors seemed to develop a resistance-like phenotype after long-term daily treatment (e.g.,>42 days) at doses of 30 to 60mg/kg. Transplantation of cell lines established fromprogressing tumors into new hosts showed that the resistant phenotype was not propagated. Furthermore, a regimen of daily metronomic uracil + tegafur (UFT, an oral 5-fluorouracil prodrug) chemotherapy with a less toxic regimen of sorafenib (15 mg/kg per day) significantly delayed the onset of resistance (>91 days). In conclusion, development of a resistance-like phenotype to sorafenib is reversible, and metronomic UFT plus sorafenib may be a promising and well-tolerated treatment for increasing efficacy by delaying emergence of such resistance. © 2010 Neoplasia Press, Inc. All rights reserved. Source

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