Synergistic interaction with arsenic trioxide and fractionated radiation in locally advanced murine tumor

Abstract

We have shown previously that arsenic trioxide (ATO) preferentially shutsdown tumor blood flow, leading to pronounced cell death in the central part of the solid tumor with a minimal effect on the surrounding normal tissues. On the basis of the histopathological and tumor perfusion studies, we hypothesized that the tumor control rate of locally advanced solid tumors would increase after the combined treatment of ATO and radiation relative to either radiation or ATO alone. The antitumor action and quantitative tumor perfusion studies were carried out with locally advanced methylcholanthrene-induced fibrosarcoma grown in BALB/c mice. The s.c. methylcholanthrene-induced fibrosarcoma leg tumors were treated with ATO alone (10 mg/kg), radiation alone (30 Gy), or drug plus radiation together. Radiation alone and drug alone delayed the growth of the tumor by a few days compared with untreated tumors. In contrast, when radiation and drug were given together, the tumor growth delay was longer than 1 month, resulting local tumor cure of 55%. The fractionated radiation combined with ATO showed a similar pronounced tumor growth delay relative to the drug alone or radiation alone. Sustained reduction in tumor blood flow after the combined treatment measured using a rubidium uptake method paralleled enhanced tumor response. There was an immediate 10-fold increase in the production of tumor necrosis factor-alpha in the tumor tissue after the drug treatment, concomitant with the onset of prompt reduction of the tumor blood flow. The present results indicate that tumor response was better with combined treatment than with either treatment alone, suggesting that ATO has potential as an adjuvant to radiotherapy.