Melanoma therapy via peptide-targeted {alpha}-radiation.

Abstract

PURPOSE:

The therapeutic efficacy of a unique melanoma-targeting peptide conjugated with an in vivo generated alpha-particle-emitting radionuclide was evaluated in the B16/F1 mouse melanoma animal model. alpha-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(Arg(11))CCMSH, was radiolabeled with (212)Pb, the parent of (212)Bi, which decays via alpha and beta decay. Biodistribution and therapy studies were done in the B16/F1 melanoma-bearing C57 mouse flank tumor model.

RESULTS:

(212)Pb[DOTA]-Re(Arg(11))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/muCi (212)Pb administered. Treatment of melanoma-bearing mice with 50, 100, and 200 muCi of (212)Pb[DOTA]-Re(Arg(11))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 muCi doses survived the study disease-free.

CONCLUSIONS:

Treatment of B16/F1 murine melanoma-bearing mice with (212)Pb[DOTA]-Re(Arg(11))CCMSH significantly decreased tumor growth rates resulting in extended mean survival times, and in many cases, complete remission of disease. (212)Pb-DOTA-Re(Arg(11))CCMSH seems to be a very promising radiopharmaceutical for targeted radionuclide therapy of melanoma.

• Authors: Yubin Miao, Mark Hylarides, Darrell R Fisher, Tiffani Shelton, Herbert Moore, Dennis W Wester, Alan R Fritzberg, Christopher T Winkelmann, Timothy Hoffman, Thomas P Quinn
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 15 Pg. 5616-21 (Aug 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16061880 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (Cys(3,4,10),D-Phe(7))alpha-MSH(3-13)
• Organometallic Compounds
• Peptides
• alpha-MSH

Topics

• Alpha Particles
• Animals
• Kidney (pathology)
• Melanoma (drug therapy, radiotherapy)
• Melanoma, Experimental
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Organometallic Compounds (pharmacokinetics)
• Peptides (chemistry, therapeutic use)
• Radiation, Ionizing
• Radiometry
• Radiotherapy (methods)
• Remission Induction
• Time Factors
• alpha-MSH (analogs & derivatives, pharmacokinetics)