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

Radiolabeled somatostatin analogs have demonstrated effectiveness for targeted radiotherapy of somatostatin receptor‐positive tumors in both tumor‐bearing rodent models and humans. A radionuclide of interest for cancer therapy is reactor‐produced 177Lu (t1/2 = 6.64 d; β− [100%]). The high therapeutic efficacy of the somatostatin analog 177Lu‐DOTA‐Tyr3‐octreotate (DOTA‐Y3‐TATE, where DOTA is 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) was previously demonstrated in a tumor‐bearing rat model (Erion et al., J. Nucl. Med. 1999;40:223P; de Jong et al., Int. J. Cancer, 2001; 92:628–633). In the current study, the toxicity and dosimetry of 177Lu‐DOTA‐Y3‐TATE were determined in both normal and tumor‐bearing rats. Doses of 177Lu‐DOTA‐Y3‐TATE ranging from 0 to 123 mCi/kg were administered to rats and complete blood counts (CBCs) and blood chemistries were analyzed out to 6 weeks. No overt signs of toxicity were observed with 177Lu‐DOTA‐Y3‐TATE (i.e., lethargy, weight loss, scruffy coat or diarrhea) at any of the dose levels. Blood chemistries and CBCs were normal except for the white blood cell counts, which showed a dose‐dependent decrease. The maximum tolerated dose was not reached at 123 mCi/kg. The biodistribution of 177Lu‐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 177Lu‐DOTA‐Y3‐TATE is an effective targeted radiotherapy agent at levels that show minimal toxicity in this rat model. © 2001 Wiley‐Liss, Inc.