Preferential action of arsenic trioxide in solid-tumor microenvironment enhances radiation therapy.
OBJECTIVE
To investigate the effect of arsenic trioxide, Trisenox (TNX), on primary cultures of endothelial cells and tumor tissue under varying pH and pO(2) environments and the effects of combined TNX and radiation therapy on experimental tumors.


METHODS
Human dermal microvascular endothelial cells were cultured in vitro and exposed to TNX under various combinations of aerobic, hypoxic, neutral, or acidic conditions, and levels of activated JNK MAP kinase were assessed by Western blotting. FSaII fibrosarcoma cells grown in the hind limb of female C3H mice were used to study the effect of TNX on tumor blood perfusion and oxygenation. The tumor-growth delay after a single or fractionated irradiation with or without TNX treatment was assessed.


RESULTS
A single intraperitoneal injection of 8 mg/kg TNX reduced the blood perfusion in FSaII tumors by 53% at 2 hours after injection. To increase the oxygenation of the tumor vasculature during TNX treatment, some animals were allowed to breathe carbogen (95% O(2)/5% CO(2)). Carbogen breathing alone for 2 hours reduced tumor perfusion by 33%. When carbogen breathing was begun immediately after TNX injection, no further reduction occurred in tumor blood perfusion at 2 hours after injection. In vitro, TNX exposure increased activity JNK MAP kinase preferentially in endothelial cells cultured in an acidic or hypoxic environment. In vivo, the median oxygenation in FSaII tumors measured at 3 or 5 days after TNX injection was found to be significantly elevated compared with control tumors. Subsequently, radiation-induced tumor-growth delay was synergistically increased when radiation and TNX injection were fractionated at 3-day or 5-day intervals.


CONCLUSIONS
Trisenox has novel vascular-damaging properties, preferentially against endothelium in regions of low pH or pO(2), which leads to tumor cell death and enhancement of the response of tumors to radiotherapy.
Griffin
Robert J
RJ
Department of Therapeutic Radiology, University of Minnesota Medical School, Minneapolis, USA. griff007@umn.edu
Williams
Brent W
BW
Park
Heon Joo
HJ
Song
Chang W
CW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006863:Hydrogen-Ion Concentration; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D010087:Oxides / Q000494:pharmacology*; D010100:Oxygen / Q000008:administration & dosage / Q000378:metabolism; D010101:Oxygen Consumption / Q000528:radiation effects*; D010313:Partial Pressure; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D011838:Radiation-Sensitizing Agents; D002245:Carbon Dioxide; C011700:carbogen; D048031:JNK Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide; D010100:Oxygen