Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours

Abstract

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.

Angiogenesis: An update and potential drug approaches (Review)

“…The mechanism through which arsenic trioxide elicits its vascular effects is, as yet, unknown and such effects have only been observed at doses close to the MTD in rodent tumor models (143). However, ADH-1 is a cyclic pentapeptide that competitively antagonizes N-cadherin which mediates cell adhesion between endothelial cells as well as between endothelial cells and pericytes within the tumor vasculature.…”

Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies

“…Numerous studies have examined the combination of VDAs and heat. The VDAs include TNF (74,75), ATO (80,212), vinblastine (78), FAA (81,124,213), DMXAA (99), and CA4P (78,214,215). All resulted in an enhancement of the heat response.…”

Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-α delivery

“…The jigs bearing the mice were then placed on a Plexiglas shelf positioned over a water bath, and the anchored legs were immersed into water preheated to 42.5jC by a precisely controlled heating unit with an accuracy of F0.1jC. The temperature in the tumors during heating is typically 0.3jC to 0.5jC below the water temperature, depending on exact point in tumor (8). However, it is possible that in PT-cAu-TNF-a -treated tumors, the heating was slightly higher because of blood flow shutdown.…”

“…as therapeutic adjuvants to low-and moderate-temperature hyperthermia (7 -10). These adjuvants predominantly target the vasculature and accentuate the thermal injury by various mechanisms like altering the blood flow or inhibiting the heat shock protein response, to name a few (8,11).…”

“…The purpose of this study was to determine whether a combination of nanoparticleassisted TNF-a delivery and hyperthermia at temperatures used clinically, and likely to occur at the tumor periphery of thermal ablation protocols, increases tumor destruction compared with hyperthermia alone in an animal tumor model. The treatment outcomes were assessed using a variety of well-accepted measures: in vitro tumor cell survival, in vivo/in vitro tumor cell survival, and tumor growth delay (8,26). In addition, to gain insight into the physiologic mechanism of TNF-a-induced tumor damage and thermal sensitization, the effect of PT-cAu-TNF-a on blood flow in tumor and normal tissues was studied using contrast enhanced ultrasonography and isotopic methods.…”