title: Melanoma therapy via peptide-targeted {alpha}-radiation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
authors.forename: Mark
authors.initials: M
authors.lastname: Hylarides
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Tiffani
authors.initials: T
authors.lastname: Shelton
authors.forename: Herbert
authors.initials: H
authors.lastname: Moore
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wester
authors.forename: Alan R
authors.initials: AR
authors.lastname: Fritzberg
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Winkelmann
authors.forename: Timothy
authors.initials: T
authors.lastname: Hoffman
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Quinn
mesh_terms: D000512:Alpha Particles; D000818:Animals; D007668:Kidney / Q000473:pathology; D008545:Melanoma / Q000188:drug therapy* / Q000532:radiotherapy*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D011839:Radiation, Ionizing; D011874:Radiometry; D011878:Radiotherapy / Q000379:methods*; D012074:Remission Induction; D013997:Time Factors; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C444302:1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (Cys(3,4,10),D-Phe(7))alpha-MSH(3-13); D009942:Organometallic Compounds; D010455:Peptides; D000521:alpha-MSH