In vivo evaluation of 188Re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy
✍ Scribed by Yubin Miao; Nellie K. Owen; Donna Whitener; Fabio Gallazzi; Timothy J. Hoffman; Thomas P. Quinn
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- French
- Weight
- 200 KB
- Volume
- 101
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
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.