T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer.
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.
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
Hori
Akira
A
Kanzaki
Naoyuki
N
Hiramatsu
Kenichi
K
Mizumoto
Makiko
M
Nakashima
Hideki
H
Yamamoto
Naoki
N
Otaka
Akira
A
Fujii
Nobutaka
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
C477728:4-fluorobenzoyl-TN-14003; D000970:Antineoplastic Agents; C515370:CCR7 protein, human; C515255:CXCL12 protein, human; C515371:Ccr7 protein, mouse; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D009842:Oligopeptides; D010455:Peptides; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; C116977:T140 peptide