On metronomic chemotherapy: modulation of angiogenesis mediated by VEGE-A

• Tumors are angiogenesis dependent. Preclinical studies have shown that well-tolerated continuous low dose, i.e. metronomic, chemotherapy can exert significant antiangiogenic effects per se and thereby a greater antitumor influence than conventional chemotherapy with high, spaced-out bolus doses. There are however, no means of quantitatively assessing the antiangiogenic effect of chemotherapy in tumors. We therefore used a surrogate tumor-free, non-surgical rat mesentery model and quantitatively studied the dose effect of metronomic treatment with cisplatin, cyclophosphamide, doxorubicin, fluorouracil and paclitaxel on VEGF-A-mediated angiogenesis, a characteristic of tumors. Cyclophosphamide and paclitaxel treatment exerted significant dose-dependent antiangiogenic effects, whereas doxorubicin treatment produced insignificant effects. By contrast, metronomic cisplatin and fluorouracil treatment occasionally significantly stimulated angiogenesis in a dose-dependent, non-linear manner. To our knowledge, this is the first report of metronomic chemotherapy stimulating angiogenesis in vivo. The data suggest that the angiogenic response to cisplatin, cyclophosphamide, fluorouracil and paclitaxel was significantly influenced by the presence of antioxidants in the vehicles or when co-treated with N-acetylcystein, a widely used free-radical scavenger. The data relating to the metronomic scheduling were compared with bolus treatment data for the identical agent formulations in the same experimental model. Cisplatin, cyclophosphamide and paclitaxel caused approximately the same overall, agent-specific angiogenesis-modulating effects following metronomic and bolus treatments. Moreover, apparently secondary delayed effects of chemotherapy affected capillary sprouting.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Acetylcysteine/pharmacology

Angiogenesis Inhibitors/*administration & dosage

Animals

Antineoplastic Agents/*administration & dosage

Dose-Response Relationship

Drug

Endothelial Cells/physiology

Male

Neoplasms/blood supply

Neovascularization

Pathologic/drug therapy

Neovascularization

Physiologic/*drug effects

Oxidative Stress

Rats

Rats

Sprague-Dawley

Stem Cells/physiology

Vascular Endothelial Growth Factor A/*physiology

Weight Gain/drug effects

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)