RAD inhibition of sarcoma growth: implications for laryngeal transplantation☆

Abstract 

Purpose

Laryngeal transplantation has not been widely accepted because of concerns regarding accelerated tumor recurrences in the setting of nonspecific immunosuppression. Allotransplantation could potentially be offered to patients if immunosuppressive therapy could be demonstrated to exert tumor suppressive properties. Preliminary reports have demonstrated an antiproliferative effect of everolimus (RAD), a derivative of the immunosuppressant rapamycin.

Materials and methods

Forty-five 10-week-old inbred C57BL/6N (B6) mice were injected subcutaneously with 1 × 10⁶ MCA205 sarcoma cells. On the third postinoculation day, the mice were divided into 4 treatment groups, undergoing daily gavage with RAD at 0, 0.2, 1.0, and 5.0 mg/kg per day for 10 consecutive days. Thereafter, treatment with RAD was discontinued and tumor size was measured every 2 days during treatment and biweekly until sacrifice on the 31st postinoculation day. Whole-blood trough levels (C_min) were measured for each group.

Results

Mean tumor diameter among the control animals and the mice treated with RAD 0.2 mg/kg per day demonstrated no significant difference (P > .07). Groups treated with RAD 1 and 5 mg/kg per day demonstrated significant growth inhibition between the 7th and the 23rd postinoculation days (P < .0001), with no significant differences being noted between these two groups (P > .09). Mean tumor suppressive whole-blood C_min's for the 1 and 5 mg/kg per day groups were 75.6 and 368.9 pg/μL, respectively.

Conclusions

RAD delivered at immunosuppressive doses of 1 and 5 mg/kg per day resulted in significant growth restriction of a fibrosarcoma in a murine model.