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Melanoma Therapy via Peptide-Targeted -Radiation

Authors' Affiliations: Departments of ¹ Biochemistry, ² Internal Medicine, ³ Radiology, and ⁴ Veterinary Pathobiology, University of Missouri-Columbia, ⁵ Harry S. Truman Veterans Administration Hospital, Columbia, Missouri; ⁶ AlphaMed, Inc., Acton, Massachusetts; and ⁷ Pacific Northwest National Laboratory, Richland, Washington

Requests for reprints: Thomas P. Quinn, 117 Schweitzer Hall, Department of Biochemistry, University of Missouri-Columbia, Columbia, MO 65211. Phone: 573-882-6099; Fax: 573-884-4812; E-mail: quinnt{at}missouri.edu.

Purpose: The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated -particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. -Radiation is densely ionizing, resulting in high concentrations of destructive radicals and irreparable DNA double-strand breaks. This high linear energy transfer overcomes radiation-resistant tumor cells and oxygen effects resulting in potentially high therapeutic indices in tumors such as melanoma.

Experimental Design: The melanoma targeting peptide, 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-Re(Arg¹¹)CCMSH, was radiolabeled with ²¹²Pb, the parent of ²¹²Bi, which decays via and ß decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model.

Results: ²¹²Pb[DOTA]-Re(Arg¹¹)CCMSH exhibited rapid tumor uptake and extended retention coupled with rapid whole body disappearance. Radiation dose delivered to the tumor was estimated to be 61 cGy/µCi ²¹²Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 µCi of ²¹²Pb[DOTA]-Re(Arg¹¹)CCMSH extended their mean survival to 22, 28, and 49.8 days, respectively, compared with the 14.6-day mean survival of the placebo control group. Forty-five percent of the mice receiving 200 µCi doses survived the study disease-free.

Conclusions: Treatment of B16/F1 murine melanoma–bearing mice with ²¹²Pb[DOTA]-Re(Arg¹¹)CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. ²¹²Pb-DOTA-Re(Arg¹¹)CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.

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