Toxicity and dosimetry of Lu-177-DOTA-Y3-octreotate in a rat model

Radiolabeled somatostatin analogs have demonstrated effectiveness for targe ted radiotherapy of somatostatin receptor-positive tumors in both tumor-bea ring rodent models and humans. A radionuclide of interest for cancer therap y is reactor-produced Lu-177 (t(1/)2 = 6.64 d; beta (-) [100%]). The high t herapeutic efficacy of the somatostatin analog Lu-177-DOTA-Tyr(3)-octreotat e (DOTA-Y3-TATE, where DOTA is 1,4,7, 10-tetraazacyclododecane-1,4,7,10-tet raacetic acid) was previously demonstrated in a tumor-bearing rat model (Er ion et al., J. Nucl. Med. 1999;40:223P; de Jong et al., Int. J. Cancer, 200 1; 92:628-633). In the current study, the toxicity and dosimetry of Lu-177- DOTA-Y3-TATE were determined in both normal and tumor-bearing rats. Doses o f Lu-177-DOTA-Y3-TATE ranging from 0 to 123 mCi/kg were administered to rat s and complete blood counts (CBCs) and blood chemistries were analyzed out to 6 weeks. No overt signs of toxicity were observed with Lu-177-DOTA-Y3-TA TE (i.e., lethargy, weight loss, scruffy coat or diarrhea) at any of the do se levels. Blood chemistries and CBCs were normal except for the white bloo d cell counts, which showed a dose-dependent decrease. The maximum tolerate d dose was not reached at 123 mCi/kg. The biodistribution of Lu-177-DOTA-Y3 -TATE was determined in CA20948 rat pancreatic tumor-bearing rats, and the data were used to estimate human absorbed doses to normal tissues. The dose -limiting organ was determined to be the pancreas, followed by the adrenal glands. The absorbed dose to the rat CA20948 tumor was estimated to be 336 rad/mCi (91 mGy/MBq). These data demonstrate that Lu-177-DOTA-Y3-TATE is an effective targeted radiotherapy agent at levels that show minimal toxicity in this rat model. (C) 2001 Wiley-Liss, Inc.