Carol A Nelson1, Michael T Azure2, Christopher T Adams3, Kurt R Zinn2. 1. Translational Medicine Consulting, Westford, Massachusetts Department of Research and Development, Andarix Pharmaceuticals, Watertown, Massachusetts; and pharmacologyconsultants@gmail.com. 2. Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama. 3. Department of Research and Development, Andarix Pharmaceuticals, Watertown, Massachusetts; and.
Abstract
UNLABELLED: P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor xenograft mice to determine whether (188)Re-P2045 could inhibit the growth of pancreatic cancer in an animal model. METHODS: (188)Re-P2045 was intravenously administered every 3 d for 16 d to nude mice with AR42J tumor xenografts that were approximately 20 mm(3) at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy, all tissues were assessed for levels of radioactivity and evaluated for histologic abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of nonradioactive (185/187)Re-P2045 for somatostatin receptors was compared in human NCI-H69 and rat AR42J tumor cell membranes expressing predominantly SSTR2. RESULTS: In the 1.85- and 5.55-MBq groups, tumor growth was inhibited in a dose-dependent fashion. In the 11.1-MBq group, tumor growth was completely inhibited throughout the dosing period and for 12 d after the last administered dose. The radioactivity level in tumors 4 h after injection was 10 percentage injected dose per gram, which was 2-fold higher than in the kidneys. (188)Re-P2045 was well tolerated in all dose groups, with no adverse clinical, histologic, or hematologic findings. The nonradioactive (185/187)Re-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rat tumor membranes, suggesting that these studies are relevant to human studies. CONCLUSION: (188)Re-P2045 is a promising therapeutic candidate for patients with somatostatin receptor-positive cancer.
UNLABELLED: P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor xenograft mice to determine whether (188)Re-P2045 could inhibit the growth of pancreatic cancer in an animal model. METHODS: (188)Re-P2045 was intravenously administered every 3 d for 16 d to nude mice with AR42J tumor xenografts that were approximately 20 mm(3) at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy, all tissues were assessed for levels of radioactivity and evaluated for histologic abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of nonradioactive (185/187)Re-P2045 for somatostatin receptors was compared in humanNCI-H69 and rat AR42J tumor cell membranes expressing predominantly SSTR2. RESULTS: In the 1.85- and 5.55-MBq groups, tumor growth was inhibited in a dose-dependent fashion. In the 11.1-MBq group, tumor growth was completely inhibited throughout the dosing period and for 12 d after the last administered dose. The radioactivity level in tumors 4 h after injection was 10 percentage injected dose per gram, which was 2-fold higher than in the kidneys. (188)Re-P2045 was well tolerated in all dose groups, with no adverse clinical, histologic, or hematologic findings. The nonradioactive (185/187)Re-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rattumor membranes, suggesting that these studies are relevant to human studies. CONCLUSION: (188)Re-P2045 is a promising therapeutic candidate for patients with somatostatin receptor-positive cancer.
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