Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP115) Thermoradiotherapy enhancement with anti-vascular strategy.

Griffin, Robert*,1, Williams, Brent1, Park, Heon Joo1, Song, Chang1, 1 Radiation Biology Section, Department of Radiation Oncology, Minneapolis, MN, USA

ABSTRACT- Introduction/objective: Arsenic trioxide (ATO, Trisenox) is a potent anti-vascular agent and significantly enhances hyperthermia or radiation response. From our earlier findings, we concluded that selective tumor vascular shutdown caused by ATO induced heat sensitivity, necrosis in hypoxic regions and pO2 increases in viable tumor. In the present study, we have combined all three modalities in sequences expected to be optimal. Results: FSaII fibrosarcoma tumors (averaging 200 cubic mm) grown in C3H mic treated with 20 Gy followed by injection with 8 mg/kg ATO and 2h later tumors heated at 42.5C did not result in significant tumor growth delay when compared to tumors that were irradiated and heated. However, when SCK mammary carcinoma grown in A/J mice was irradiated with 20 Gy, 8 mg/kg ATO and 2 h later the tumors heated at 41.5C for 60 min, 90% were cured, while heat or radiation alone or combined groups produced 20-40% tumor cure. Subsequently, the effectiveness of fractionated trimodality treatment against FSaII and SCK tumors was studied. Each treatment arm now contains data from 5-10 individual animals. Trimodality treatment repeated using a 5 Gy irradiation to FSaII and SCK tumors every 3 or 5 days significantly increased tumor regression and growth delay. For example, there was a 10 day delay for FSaII tumors treated every 3 days with 5 Gy, 8 mg/kg ATO and 42.5C for 60 min compared to 5 Gy combined with heat alone. There were also 20% of FSaII tumors that completely regressed in the trimodality group compared to 0% in other treatments. Interestingly, ATO given at 4 mg/kg was nearly effective as 8 mg/kg in the trimodality regimen. In the SCK tumor, there was a 20 day delay in tumor regrowth in the trimodality treatment arm and 43% of tumors completely regressed compared to 30% regression in tumors treated with radiation and ATO and 14% regression in the group treated with heat and radiation. We are continuing our investigation using smaller fraction size, lower doses of ATO and studying endothelial cell apoptosis after treatment. Conclusions: These results suggest fractionated radiation with arsenic trioxide and clinically achievable thermal doses as a viable option against tumors that may not be susceptible to mono or dual-treatment regimens. Supported by NCI CA44114 and Cell Therapeutics, Inc, Seattle, WA.

Key words: anti-vascular, thermal therapy, fractionation, radiosensitization

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2005 RRS