title: Inhibition of growth and metastasis of orthotopic human prostate cancer in athymic mice by combination therapy with pegylated interferon-alpha-2b and docetaxel.
abstract: We evaluated whether treatment of orthotopic human prostate cancer in nude mice with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) and docetaxel could represent a two-compartment targeting of primary tumor (tumor cells and tumor-associated endothelial cells) and inhibition of regional lymph node metastasis. The antiangiogenic properties of IFN were combined with the cytotoxic properties of docetaxel, resulting in apoptosis of both tumor cells and endothelium and hence significant inhibition of primary tumor growth. We first determined the optimal biological dose of PEG-IFN-alpha-2b (70,000 IU/week) necessary to down-regulate the expression of basic fibroblast growth factor, matrix metalloprotease-9, and matrix metalloprotease-2. The therapeutic dose of docetaxel (10 mg/kg/week) was determined by efficacy and minimal body weight loss. Therapy beginning 3 days after orthotopic implantation of PC3-MM2 prostate cancer cells reduced tumor weight by 37% in mice treated with PEG-IFN-alpha-2b, by 60% in mice treated with docetaxel, and by 83% in those given both drugs. PEG-IFN-alpha-2b also induced apoptosis of tumor-associated endothelial cells and hence a significant decrease in microvessel density. Our data indicate that the combination of PEG-IFN-alpha and docetaxel inhibits neoplastic angiogenesis by inducing a decrease in the local production of proangiogenic molecules by tumor cells, resulting in increased apoptosis of tumor-associated endothelial cells.
authors.affiliation: Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Huang
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Anh T
authors.initials: AT
authors.lastname: Lee
authors.forename: Takashi
authors.initials: T
authors.lastname: Karashima
authors.forename: Cora
authors.initials: C
authors.lastname: Bucana
authors.forename: Daniel
authors.initials: D
authors.lastname: Kedar
authors.forename: Paul
authors.initials: P
authors.lastname: Sweeney
authors.forename: Badar
authors.initials: B
authors.lastname: Mian
authors.forename: Dominic
authors.initials: D
authors.lastname: Fan
authors.forename: David
authors.initials: D
authors.lastname: Shepherd
authors.forename: Isaiah J
authors.initials: IJ
authors.lastname: Fidler
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
authors.forename: Jerald J
authors.initials: JJ
authors.lastname: Killion
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D011994:Recombinant Proteins; D043823:Taxoids; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D015820:Cadherins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D043823:Taxoids; D016222:Fibroblast Growth Factor 2; D000077143:Docetaxel; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel; C100416:peginterferon alfa-2a