Low-dosage metronomic chemotherapy and angiogenesis: topoisomerase inhibitors irinotecan and mitoxantrone stimulate VEGF-A-mediated angiogenesis

• Published in: APMIS : acta pathologica, microbiologica et immunologica Scandinavica microbiologica et immunologica Scandinavica, 2012-02, Vol.120 (2), p.147-156
• Main Authors: ALBERTSSON, PER, LENNERNäS, BO, NORRBY, KLAS
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Biological and medical sciences; Body Weight - physiology; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cancer and Oncology; Cancer och onkologi; Chemotherapy; eactive oxygen species; Endothelial Cells - drug effects; Fundamental and applied biological sciences. Psychology; Infectious diseases; irinotecan; Male; Medical research; Medical sciences; Mesentery - blood supply; metronomic chemotherapy; Microbiology; mitoxantrone; Mitoxantrone - pharmacology; Neovascularization, Pathologic - drug therapy; Neovascularization, Physiologic - drug effects; rat; Rats; Rats, Sprague-Dawley; reactive oxygen species; Rodents; Statistics, Nonparametric; Topoisomerase Inhibitors - pharmacology; Vascular Endothelial Growth Factor A - metabolism; VEGF
• ISSN: 0903-4641; 1600-0463; 1600-0463
• DOI: 10.1111/j.1600-0463.2011.02830.x

Albertsson P, Lennernäs B, Norrby K. Low‐dosage metronomic chemotherapy and angiogenesis: topoisomerase inhibitors irinotecan and mitoxantrone stimulate VEGF‐A‐mediated angiogenesis. APMIS 2011. Metronomic chemotherapy with cytotoxic agents has been shown to inhibit angiogenesis and, consequently, tumor growth by targeting vascular endothelial cells (ECs). In these regimens, anti‐tumor activities additional to anti‐angiogenesis may operate. Moreover, chemotherapy typically generates reactive oxygen species in targeted ECs, which can affect angiogenesis. The aim of the present study was to assess the systemic effect of low‐dosage metronomic treatment with either irinotecan or mitoxantrone on angiogenesis induced by VEGF‐A. Angiogenesis was induced in normal adult rat mesentery by intraperitoneal injection of a low dosage of VEGF‐A. Thereafter, irinotecan and mitoxantrone were infused separately continuously at minimally toxic dosages for 14 consecutive days via a subcutaneous osmotic minipump. Angiogenesis was assessed in terms of objective and quantitative variables using morphologic and computerized image analyses. Irinotecan or mitoxantrone significantly stimulated angiogenesis, with ironotecan increasing angiogenesis by 104%, when compared with the vehicle‐treated animals. Low‐dosage metronomic chemotherapy with irinotecan or mitoxantrone stimulates angiogenesis in the normal mesentery of rats, probably by inducing low‐level oxidative stress in the targeted ECs. Whether or not this pertains to tumor angiogenesis may be difficult to confirm, as several anti‐tumor modes may operate during low‐dosage metronomic chemotherapy.