The camptothecin derivative CPT-11 inhibits angiogenesis in a dual-color imageable orthotopic metastatic nude mouse model of human colon cancer.
Recent studies have shown the expression of a stem cell marker protein, nestin, in nascent blood vessels in nestin-driven green fluorescent protein (ND-GFP) transgenic nude mice. In the present study, we visualized tumor angiogenesis and evaluated the antiangiogenic efficacy of CPT-11 in ND-GFP nude mice using dual-color fluorescence imaging. We orthotopically implanted ND-GFP nude mice with the human cancer cell line HCT-116 expressing red fluorescent protein (RFP). The mice were treated with CPT-11 at 40 mg/kg on days 7, 10, 14. Tumor angiogenesis was imaged and visualized by dual-color fluorescence imaging on day 17, three days after the last CPT-11 treatment. Tumor volume and the mean nascent blood vessel density were determined and compared to the control mice. The growing tumor had high expressions of nestin in the nascent blood vessels. The nascent blood vessels showed co-localization of the endothelial-cell-specific marker CD-31 under immunohistochemical staining. The nascent blood vessels were highly visible and their density was determined. ND-GFP nude mice that were administered CPT-11 showed significant reduction in the mean nascent blood vessel density and tumor volume. The dual-color model of ND-GFP transgenic nude mice orthotopically implanted with HCT-116 expressing RFP proved to be effective in visualizing and quantitating tumor growth and tumor angiogenesis. The results showed that CPT-11 is an effective inhibitor of angiogenesis and provided strong implications for wider clinical application of CPT-11 for colon cancer.
Ji
Yong
Y
AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111, USA.
Hayashi
Katsuhiro
K
Amoh
Yasuyuki
Y
Tsuji
Kazuhiko
K
Yamauchi
Kensuke
K
Yamamoto
Norio
N
Tsuchiya
Hiroyuki
H
Tomita
Katsuro
K
Bouvet
Michael
M
Hoffman
Robert M
RM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis / Q000235:genetics; D000077146:Irinotecan; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D064231:Nestin; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000097573:Red Fluorescent Protein
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D049452:Green Fluorescent Proteins; D007381:Intermediate Filament Proteins; D000077146:Irinotecan; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D011993:Recombinant Fusion Proteins; D000097573:Red Fluorescent Protein; C577484:NES protein, human; C577485:Nes protein, mouse