Antitumor efficacy and pharmacodynamic profile of proteasome inhibition of CEP-18770 and bortezomib in MM tumor xenografts. RPMI 8226 human MM xenografts were implanted subcutaneously in SCID mice. Treatment started after establishing a palpable subcutaneous tumor (100-140 mm3). Representative intravenous and oral efficacy data are shown. (A) CEP-18770 and bortezomib were administered intravenously, twice a week for 4 weeks (2q7d×8 injections) at the doses indicated as a solution of 10% Solutol HS15/87% buffered saline/3% DMSO in a volume of 10 mL/kg body weight mouse. (B) CEP-18770 was administered orally (p.o.) in a solution of 3% DMSO, 10% Solutol, and 87% sterile NaCl 0.9% twice a week for 4 weeks at the indicated doses in a volume of 20 mL/kg body weight mouse. Tumor parameters were measured and analyzed as detailed in “Subcutaneous tumor xenograft models.” (C,D) Pharmacodynamic profile of proteasome inhibition in RPMI 8226 xenografts and normal peripheral tissues of mice at the maximum tolerated doses (MTD) of CEP-18770 and bortezomib administered intravenously in SCID mice. Time-course proteasome inhibition after a single intravenous administration was measured by an ex vivo fluorimetric kinetic assay of chymotrypsin-like activity. Proteasome percentage inhibition (PI %) in sample tissue lysates from treated versus vehicle-treated control mice was calculated as: (Slope of control tissues − slope of treated tissues) / (Slope of control tissues × 100) after normalization for protein content of tissue and hemoglobin content of whole blood. Results shown are means (± standard deviation) of 3 independent experiments (3 mice per time point).
