Inhibition of growth and metastasis of orthotopic human prostate cancer in athymic mice by combination therapy with pegylated interferon-alpha-2b and docetaxel.
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.
Huang
Samuel F
SF
Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Kim
Sun-Jin
SJ
Lee
Anh T
AT
Karashima
Takashi
T
Bucana
Cora
C
Kedar
Daniel
D
Sweeney
Paul
P
Mian
Badar
B
Fan
Dominic
D
Shepherd
David
D
Fidler
Isaiah J
IJ
Dinney
Colin P
CP
Killion
Jerald J
JJ
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
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