Narges K Tafreshi1, Christopher J Tichacek1,2,3, Darpan N Pandya4, Michael L Doligalski1, Mikalai M Budzevich5, HyunJoo Kil6, Nikunj B Bhatt4, Nancy D Kock7, Jane L Messina8,9,10, Epifanio E Ruiz5, Nella C Delva1, Adam Weaver11, William R Gibbons11, David C Boulware12, Nikhil I Khushalani13, Ghassan El-Haddad14, Pierre L Triozzi15, Eduardo G Moros1,2,3,10, Mark L McLaughlin6, Thaddeus J Wadas4, David L Morse16,3,5,10. 1. Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 2. Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 3. Department of Physics, University of South Florida, Tampa, Florida. 4. Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina. 5. Small Animal Imaging Laboratory, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 6. Department of Pharmaceutical Sciences, Health Sciences Center, West Virginia University, and Modulation Therapeutics Inc., Morgantown, West Virginia. 7. Section on Comparative Medicine, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, North Carolina. 8. Departments of Anatomic Pathology and Cutaneous Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 9. Department of Dermatology, University of South Florida, Tampa, Florida. 10. Department of Oncologic Sciences, University of South Florida, Tampa, Florida. 11. Division of Research Integrity and Compliance, University of South Florida, Tampa, Florida. 12. Biostatistics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 13. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 14. Departments of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and. 15. Department of Hematology and Oncology, Wake Forest University Health Sciences, Winston-Salem, North Carolina. 16. Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida david.morse@moffitt.org.
Abstract
New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The 225Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of 225Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of 225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. Methods: The 225Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficientmice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. Results: High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of 225Ac-DOTA-MC1RL in treated mice relative to controls. Conclusion: These results suggest significant potential for the clinical translation of 225Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
Authors: M R McDevitt; D Ma; L T Lai; J Simon; P Borchardt; R K Frank; K Wu; V Pellegrini; M J Curcio; M Miederer; N H Bander; D A Scheinberg Journal: Science Date: 2001-11-16 Impact factor: 47.728
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