期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 318, 期 3, 页码 1265-1272出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.106.104141
关键词
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资金
- Intramural NIH HHS Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [Z01DK053100, ZIADK053100] Funding Source: NIH RePORTER
Most human tumors overexpress or ectopically express peptide hormone/ neurotransmitter receptors, which are being increasingly studied as a means to selectively deliver cytotoxic agents. Although a number of peptide ligand-constructs demonstrate tumor cytotoxicity, the role of specific tumoral receptor interaction in its mediation is unclear. To address this question, we synthesized camptothecin ( CPT) bombesin ( Bn) analogs, in which CPT was coupled via a novel carbamate linker, L2 [ N-( N-methylamino-ethyl)-glycine carbamate], that were chemically similar but differed markedly in their potency/affinity for human Bn receptors. We then examined their ability to interact with Bn receptors and cause in vitro and in vivo tumor cytotoxicity. CPT-L2-[D-Tyr(6), beta-Ala(11), D-Phe(13), Nle(14)] Bn ( 6-14) ( BA3) bound with high affinity and had high potency for all three human Bn receptor subtypes, whereas CPT-L2-[ D-Tyr(6), beta-Ala(11), D-Phe(13), Nle(14)] Bn ( 6-14) [ D-Phe-CPT-L2-BA3] had > 1400-fold lower affinity/potency. I-125-CPT-L2-BA3 but not I-125-D-Phe-CPT-L2-BA3 was internalized by Bn receptor subtype-containing cells. CPT-L2- BA3 displayed significantly more cytotoxicity than D-Phe-CPT-L2-BA3 toward NCI-H1299 lung cancer cells in both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide and clonogenic assays and more potently inhibited H1299 xenograft growth in nude mice. CPT-L2- BA3 was also metabolically more stable than its parent peptide and inhibited growth of a number of other tumor cell lines in vitro and in vivo. These results demonstrate that specific tumoral receptor interaction is important in mediating the ability of peptide ligand-cytotoxic constructs to cause cytotoxicity. Because many tumors overexpress Bn receptors, these results also demonstrate that CPT-L2- BA3 will be a useful agent for delivering receptor-mediated cytotoxicity to many different human tumors.
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