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T140 analogs as CXCR4 antagonists identified as anti‐metastatic agents in the treatment of breast cancer
Author(s) -
Tamamura Hirokazu,
Hori Akira,
Kanzaki Naoyuki,
Hiramatsu Kenichi,
Mizumoto Makiko,
Nakashima Hideki,
Yamamoto Naoki,
Otaka Akira,
Fujii Nobutaka
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)00824-x
Subject(s) - cxcr4 antagonist , metastasis , cxcr4 , metastatic breast cancer , cancer research , medicine , cancer , in vitro , breast cancer , cancer cell , chemokine receptor , stromal cell , receptor , umbilical vein , chemotaxis , pharmacology , stromal cell derived factor 1 , chemokine , immunology , chemistry , biochemistry
A chemokine receptor, CXCR4, and its endogenous ligand, stromal cell‐derived factor‐1 (SDF‐1), have been recognized to be involved in the metastasis of several types of cancers. T140 analogs are peptidic CXCR4 antagonists composed of 14 amino acid residues that were previously developed as anti‐HIV agents having inhibitory activity against HIV‐entry through its co‐receptor, CXCR4. Herein, we report that these compounds effectively inhibited SDF‐1‐induced migration of human breast cancer cells (MDA‐MB‐231), human leukemia T cells (Sup‐T1) and human umbilical vein endothelial cells at concentrations of 10–100 nM in vitro. Furthermore, slow release administration by subcutaneous injection using an Alzet osmotic pump of a potent and bio‐stable T140 analog, 4F‐benzoyl‐TN14003, gave a partial, but statistically significant ( P ≤0.05 ( t ‐test)) reduction in pulmonary metastasis of MDA‐MB‐231 in SCID mice, even though no attempt was made to inhibit other important targets such as CCR7. These results suggest that T140 analogs have potential use for cancer therapy, and that small molecular CXCR4 antagonists could potentially replace neutralizing antibodies as anti‐metastatic agents for breast cancer.

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