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In vivo evaluation of 188 Re‐labeled alpha‐melanocyte stimulating hormone peptide analogs for melanoma therapy
Author(s) -
Miao Yubin,
Owen Nellie K.,
Whitener Donna,
Gallazzi Fabio,
Hoffman Timothy J.,
Quinn Thomas P.
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10640
Subject(s) - kidney , in vivo , melanoma , nephrotoxicity , peptide , pharmacokinetics , endocrinology , chemistry , medicine , pharmacology , cancer research , biology , biochemistry , microbiology and biotechnology
The purpose of our study was to optimize melanoma tumor uptake of 188 Re‐CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of 188 Re‐CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co‐infusion were investigated as strategies to improve the tumor/kidney uptake ratio of 188 Re‐CCMSH. The substitution of Lys11 with Arg11 was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of 188 Re‐CCMSH and 188 Re‐(Arg 11 )CCMSH were determined in B16/F1 murine melanoma‐bearing C57 mice. Tumor uptake values of 188 Re‐CCMSH and 188 Re‐(Arg 11 )CCMSH were 15.03 ± 5.20% ID/g and 20.44 ± 1.91% ID/g at 1 hr postinjection and 1.94 ± 0.47% ID/g and 3.50 ± 2.32% ID/g at 24 hr postinjection. Renal retention of 188 Re‐(Arg 11 )CCMSH was 11.79 ± 1.29 ID/g and 3.67 ± 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to 188 Re‐CCMSH. The Arg for Lys substitution in 188 Re‐(Arg 11 )CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both 188 Re‐CCMSH and 188 Re‐(Arg 11 )CCMSH were significantly reduced by co‐injection of 20 mg of L ‐lysine, L ‐arginine and a combination of L ‐lysine: L ‐arginine. Tumor/kidney uptake values for 188 Re‐CCMSH and 188 Re‐(Arg 11 )CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co‐injection, the tumor/kidney ratio of 188 Re‐CCMSH was lower than that of 188 Re‐(Arg 11 )CCMSH. Improved tumor uptake and reduced kidney retention of 188 Re‐(Arg 11 )CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys. © 2002 Wiley‐Liss, Inc.