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 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 beta-subunit human choriogonadotropin (beta-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.
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, Ontario, Canada.
Terence C
TC
Tang
Shan
S
Man
Christina R
CR
Lee
Ping
P
Xu
Robert S
RS
Kerbel
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D018997:Chorionic Gonadotropin, beta Subunit, Human; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008114:Liver Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D015996:Survival Rate; D005641:Tegafur / Q000008:administration & dosage; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D001557:Benzenesulfonates; D018997:Chorionic Gonadotropin, beta Subunit, Human; C511761:DC101 monoclonal antibody; D010671:Phenylurea Compounds; D011725:Pyridines; D005641:Tegafur; D009536:Niacinamide; D014498:Uracil; D004317:Doxorubicin; D003520:Cyclophosphamide; D000077157:Sorafenib