Moxifloxacin increases anti-tumor and anti-angiogenic activity of irinotecan in human xenograft tumors.
Camptothecins (CPTs) are topoisomerase I inhibitors chemotherapeutic agents used in combination chemotherapy. We showed previously that combination of moxifloxacin (MXF) and CPT induced inhibitory effects on topoisomerase I activity, on proliferation of HT-29 cells in vitro and enhanced apoptosis, compared to CPT alone. Analysis of secretion of the pro-angiogenic factors IL-8 and VEGF showed significant reduction by MXF. Using a murine model of human colon carcinoma xenograft, we compared the effects of MXF/CPT in vitro to MXF/irinotecan combination in vivo. We show that the MXF/CPT inhibitory effects observed in vitro are reflected in the inhibition of the progressive growth of HT-29 cells implanted in SCID mice. Using caliper measurements, Doppler ultrasonography, image analyses and immunohistochemistry of nuclear proteins (Ki-67) and vascular endothelial cells (CD-31) we show that addition of MXF (45mg/kg) to a relatively ineffective dose of irinotecan (20mg/kg), results in a 50% and 30% decrease, respectively, in tumor size and a decrease in Ki-67 staining. Power Doppler Ultrasound showed a significant, pronounced decrease in the number of blood vessels, as did CD-31 staining, indicating decreased blood flow in tumors in mice treated with MXF alone or MXF/irinotecan compared to irinotecan. These results suggest that the combination of MXF/irinotecan may result in enhanced anti-neoplastic/anti-angiogenic activity.
Reuveni
Debby
D
Department of Cell and Developmental Biology, Tel Aviv University, Israel.
Halperin
Drora
D
Fabian
Ina
I
Tsarfaty
Galia
G
Askenasy
Nadir
N
Shalit
Itamar
I
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D016209:Interleukin-8 / Q000032:analysis; D000077146:Irinotecan; D051379:Mice; D016513:Mice, SCID; D000077266:Moxifloxacin; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011804:Quinolines / Q000494:pharmacology*; D018608:Ultrasonography, Doppler; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D016209:Interleukin-8; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011804:Quinolines; D000077146:Irinotecan; D000077266:Moxifloxacin; D002166:Camptothecin