In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B

Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2001-02, Vol.61 (3), p.1013-1021
Main Authors: TOWLE, Murray J, SALVATO, Kathleen A, HABGOOD, Gregory J, SINGER, Lori A, DIPIETRO, Lucian V, YUAN WANG, CHEN, Jack J, QUINCY, David A, DAVIS, Ashley, YOSHIMATSU, Kentaro, KISHI, Yoshito, YU, Melvin J, BUDROW, Jacqueline, LITTLEFIELD, Bruce A, WELS, Bruce F, KUZNETSOV, Galina, AALFS, Kimberley K, WELSH, Susan, WANJUN ZHENG, SELETSKY, Boris M, PALME, Monica H
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Biotin - analogs & derivatives
Biotin - metabolism
Biotin - pharmacology
Biotinylation
Cell Division - drug effects
Chemotherapy
Drug Screening Assays, Antitumor
Ethers, Cyclic - pharmacology
Female
Furans
G2 Phase - drug effects
Growth Inhibitors - pharmacology
Heterocyclic Compounds, 4 or More Rings - pharmacology
Humans
Ketones - pharmacology
Macrolides
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Mitosis - drug effects
Pharmacology. Drug treatments
Spindle Apparatus - drug effects
Tubulin - metabolism
Tubulin Modulators
Tumor Cells, Cultured - drug effects
Xenograft Model Antitumor Assays
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Summary:Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues that retain the remarkable potency of the parent compound. In this study, we show that two macrocyclic ketone analogues of halichondrir B, ER-076349 and ER-086526, have sub-nM growth inhibitory activities in vitro against numerous human cancer cell lines as well as marked in vivo activities at 0.1-1 mg/kg against four human xenografts: MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer. ER-076349 and ER-086526 induce G2-M cell cycle arrest and disruption of mitotic spindles, consistent with the tubulin-based antimitotic mechanism of halichondrin B. This is supported further by direct binding of the biotinylated analogue ER-040798 to tubulin and inhibition of tubulin polymerization in vitro by ER-076349 and ER-086526. Retention of the extraordinary in vitro and in vivo activity off halichondrin B in structurally simplified, fully synthetic analogues establishes the feasibility of developing halichondrin B-based agents as highly effective, novel anticancer drugs.
ISSN:0008-5472
1538-7445