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Impact of Endothelin Axis Modification in Cancer Immunotherapy and Transplantation in Murine Model
Jeffrey P Wolters, P. Joseph Yannie, Ekaterine Goliadze, Maryellen Dolat, Georgi Guruli
Virginia Commonwealth University, Richmond,, VA

Introduction: The aim of this study was to determine if modification of the endothelin axis would alter the growth of murine prostate cancer as well as murine skin graft survivability.
Materials & Methods: One group of mice were injected with RM1 (prostate cancer) cells subcutaneously. Modified dendritic cells (DC) were injected into the contralateral flank. We used TNFa, BQ788 (ETB receptor antagonist) and RM1 cell lysates for DC modification. In transplant experiments, Balb/C mice received an allographic skin transplant from C57B/6 mice and were treated either with BQ123(ETA receptor antagonist) or water. Grafts were considered dead when complete separation was noted.
Results: In the prostate cancer experiment the mice were treated with DC alone (1), DC+TNFa(2), DC+RM1 lysate (3), DC+TNF+ BQ788 (4), and TNFa+BQ788+RM1 lysate (5). By day 28, mean tumor size reached 1824.08+229.86 mm3 in the Group 1, 1845.42+302.34 mm3 in the Group 2, 1502.67+367.13 mm3 in the Group 3, 1400.16+188.88 mm3 in Group 4, and 922.58+90.86 mm3 in Group 5. Difference in tumor sizes between Groups 1 and 5 was statistically significant (P=0.002). In the transplant experiment graft survival was 11.0+0.7 days in control group and 15.8+1.1 days in the group treated with BQ123 (P<0.001).

Conclusions:
We have shown for the first time that modification of the endothelin axis on dendritic cells might alter immune response and prolong graft survival. Further, ETB receptor blockade seems to stimulate proinflammatory immune response, a feature that may be useful in the treatment of malignant tumors.


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