Preclinical Investigation of 212Pb-DOTAMTATE for Peptide Receptor Radionuclide Therapy in a Neuroendocrine Tumor Model
| Autor: | Izabela Tworowska, Ebrahim S. Delpassand, Amal Saidi, Tania Stallons, Julien Torgue |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Receptors Peptide Octreotide Pharmacology Neuroendocrine tumors Article Heterocyclic Compounds 1-Ring Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Acetamides medicine Animals Humans Receptor Radioisotopes Octreotate Somatostatin receptor business.industry Ascorbic acid medicine.disease Neuroendocrine Tumors 030104 developmental biology Somatostatin Lead Oncology chemistry 030220 oncology & carcinogenesis Radionuclide therapy Fluorouracil Radiopharmaceuticals business medicine.drug |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-18-1103 |
| Popis: | Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212Pb-DOTAMTATE, the octreotate analogue, in combination with 212Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of 212Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including l-lysine and l-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. 212Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 μCi showing 100% survival and with nontoxic cumulative doses up to 45 μCi, when fractionated into three smaller doses of 15 μCi. In an initial efficacy study, a single 10 μCi injection of 212Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of 212Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 μCi 212Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that 212Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications. |
| Databáze: | OpenAIRE |
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