Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma
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 immunodeficient mice; however, these...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2010-03-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558610801058 |
| _version_ | 1818755716351000576 |
|---|---|
| author | Terence C. Tang Shan Man Christina R. Lee Ping Xu Robert S. Kerbel |
| author_facet | Terence C. Tang Shan Man Christina R. Lee Ping Xu Robert S. Kerbel |
| author_sort | Terence C. Tang |
| collection | DOAJ |
| description | 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 immunodeficient mice; 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 transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was 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 toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic 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. |
| first_indexed | 2024-12-18T05:43:34Z |
| format | Article |
| id | doaj.art-35d0bf024a5b4449a582419bf06e5ed1 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-18T05:43:34Z |
| publishDate | 2010-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-35d0bf024a5b4449a582419bf06e5ed12022-12-21T21:19:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022010-03-0112326427410.1593/neo.91872Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular CarcinomaTerence C. Tang0Shan Man1Christina R. Lee2Ping Xu3Robert S. Kerbel4Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaMolecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaMolecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaMolecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaMolecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, Toronto, Ontario, CanadaHepatocellular 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 immunodeficient mice; 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 transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was 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 toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic 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.http://www.sciencedirect.com/science/article/pii/S1476558610801058 |
| spellingShingle | Terence C. Tang Shan Man Christina R. Lee Ping Xu Robert S. Kerbel Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma Neoplasia: An International Journal for Oncology Research |
| title | Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma |
| title_full | Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma |
| title_fullStr | Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma |
| title_full_unstemmed | Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma |
| title_short | Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma |
| title_sort | impact of metronomic uft cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S1476558610801058 |
| work_keys_str_mv | AT terencectang impactofmetronomicuftcyclophosphamidechemotherapyandantiangiogenicdrugassessedinanewpreclinicalmodeloflocallyadvancedorthotopichepatocellularcarcinoma AT shanman impactofmetronomicuftcyclophosphamidechemotherapyandantiangiogenicdrugassessedinanewpreclinicalmodeloflocallyadvancedorthotopichepatocellularcarcinoma AT christinarlee impactofmetronomicuftcyclophosphamidechemotherapyandantiangiogenicdrugassessedinanewpreclinicalmodeloflocallyadvancedorthotopichepatocellularcarcinoma AT pingxu impactofmetronomicuftcyclophosphamidechemotherapyandantiangiogenicdrugassessedinanewpreclinicalmodeloflocallyadvancedorthotopichepatocellularcarcinoma AT robertskerbel impactofmetronomicuftcyclophosphamidechemotherapyandantiangiogenicdrugassessedinanewpreclinicalmodeloflocallyadvancedorthotopichepatocellularcarcinoma |