Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours.
It has previously been found that the anti-leukaemia agent Arsenic Trioxide (ATO) causes vascular shutdown in solid tumours and markedly sensitizes tumours to hyperthermia. The present study was designed to evaluate the mechanism of action and dose-dependence of ATO-induced thermosensitization in FSaII and SCK murine tumours. The role of oxidative stress was studied by observing ATO-induced vascular shutdown in vivo and ATO-induced endothelial cell adhesion molecule expression in vitro in the presence or absence of an anti-oxidant. It was found that a dose as low as 2 mg/kg ATO impaired vascular function, as estimated by 86Rb uptake, in the tumour. The degree of tumour growth delay induced by 1 h of hyperthermia at 42.5 degrees C, applied 2 h after ATO injection, was proportional to the dose of ATO administered. In addition, it was found that ATO can directly thermosensitize tumour cells in vitro. The development of massive tissue necrosis in the tumour was observed in the days after treatment, especially with the combination of ATO and heating. ATO-induced adhesion molecule expression in vitro was abolished when the anti-oxidant n-acetyl-cysteine (NAC) was introduced prior to exposure, while the addition of NAC in vivo partially blocked ATO-induced vascular shutdown. These results suggest that the expression of adhesion molecules by the vasculature due to oxidative stress contribute to the ATO-induced selective tumour vascular effects observed and that the clinical use of ATO to increase tumour thermosensitivity via direct cellular and vascular effects appears feasible.
Griffin
R J
RJ
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Medical School, 420 Delaware St. S.E., MMC 494, Minneapolis, MN 55455, USA. griff007@umn.edu
Monzen
H
H
Williams
B W
BW
Park
H
H
Lee
S H
SH
Song
C W
CW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D051379:Mice; D008809:Mice, Inbred C3H; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology*; D012414:Rubidium Radioisotopes; D014471:Umbilical Veins / Q000166:cytology
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D012414:Rubidium Radioisotopes; D018799:Intercellular Adhesion Molecule-1; D000077237:Arsenic Trioxide