In vitro and in vivo activity of LS 4477 and LS 4559, novel analogues of the tubulin binder estramustine

K M Nicholson, R M Phillips, S D Shnyder, M C Bibby

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

LS 4477 and LS 4559, two of a series of N-acyl-aminoalkyl phenyl ethers, are rationally designed compounds based on the tubulin binder estramustine. This study investigated their mechanism of action and compared their effectiveness in relation to estramustine in vitro against a panel of human and murine cell lines and in vivo against two murine colon tumour models (MAC). At biologically relevant concentrations, LS 4477 and LS 4559 caused a 59.9 and 56% reduction in tubulin assembly, respectively, compared with a 28.4% reduction in tubulin assembly by estramustine. The analogues were approximately 100 times more potent in chemosensitivity tests in vitro than the parent compound. Both analogues were orally active against the MAC 15A murine tumour model, to a greater extent than estramustine, producing significant growth delays (P<0.01). Significant activity was also shown against the slower growing MAC 26 tumour for LS 4577 (the soluble pro-drug of LS 4559). The results presented in this study suggest these compounds warrant further development with a view to assessing their clinical activity.

Original languageEnglish
Pages (from-to)194-204
Number of pages11
JournalEuropean Journal of Cancer
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 2002
Externally publishedYes

Fingerprint

Estramustine
Tubulin
Phenyl Ethers
Neoplasms
Prodrugs
Colon
Cell Line
In Vitro Techniques
Growth

Cite this

@article{f13e5a4b8df44425b52c2842eaa126da,
title = "In vitro and in vivo activity of LS 4477 and LS 4559, novel analogues of the tubulin binder estramustine",
abstract = "LS 4477 and LS 4559, two of a series of N-acyl-aminoalkyl phenyl ethers, are rationally designed compounds based on the tubulin binder estramustine. This study investigated their mechanism of action and compared their effectiveness in relation to estramustine in vitro against a panel of human and murine cell lines and in vivo against two murine colon tumour models (MAC). At biologically relevant concentrations, LS 4477 and LS 4559 caused a 59.9 and 56{\%} reduction in tubulin assembly, respectively, compared with a 28.4{\%} reduction in tubulin assembly by estramustine. The analogues were approximately 100 times more potent in chemosensitivity tests in vitro than the parent compound. Both analogues were orally active against the MAC 15A murine tumour model, to a greater extent than estramustine, producing significant growth delays (P<0.01). Significant activity was also shown against the slower growing MAC 26 tumour for LS 4577 (the soluble pro-drug of LS 4559). The results presented in this study suggest these compounds warrant further development with a view to assessing their clinical activity.",
keywords = "Animals, Antineoplastic Agents, Alkylating/therapeutic use, Binding, Competitive, Colchicine/metabolism, Colonic Neoplasms/drug therapy, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Estramustine/analogs & derivatives, Inhibitory Concentration 50, Male, Mice, Microtubules/metabolism, Prodrugs, Swine, Tubulin/metabolism, Tubulin Modulators, Tumor Cells, Cultured",
author = "Nicholson, {K M} and Phillips, {R M} and Shnyder, {S D} and Bibby, {M C}",
year = "2002",
month = "1",
doi = "10.1016/S0959-8049(01)00341-0",
language = "English",
volume = "38",
pages = "194--204",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Limited",
number = "1",

}

In vitro and in vivo activity of LS 4477 and LS 4559, novel analogues of the tubulin binder estramustine. / Nicholson, K M; Phillips, R M; Shnyder, S D; Bibby, M C.

In: European Journal of Cancer, Vol. 38, No. 1, 01.2002, p. 194-204.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vitro and in vivo activity of LS 4477 and LS 4559, novel analogues of the tubulin binder estramustine

AU - Nicholson, K M

AU - Phillips, R M

AU - Shnyder, S D

AU - Bibby, M C

PY - 2002/1

Y1 - 2002/1

N2 - LS 4477 and LS 4559, two of a series of N-acyl-aminoalkyl phenyl ethers, are rationally designed compounds based on the tubulin binder estramustine. This study investigated their mechanism of action and compared their effectiveness in relation to estramustine in vitro against a panel of human and murine cell lines and in vivo against two murine colon tumour models (MAC). At biologically relevant concentrations, LS 4477 and LS 4559 caused a 59.9 and 56% reduction in tubulin assembly, respectively, compared with a 28.4% reduction in tubulin assembly by estramustine. The analogues were approximately 100 times more potent in chemosensitivity tests in vitro than the parent compound. Both analogues were orally active against the MAC 15A murine tumour model, to a greater extent than estramustine, producing significant growth delays (P<0.01). Significant activity was also shown against the slower growing MAC 26 tumour for LS 4577 (the soluble pro-drug of LS 4559). The results presented in this study suggest these compounds warrant further development with a view to assessing their clinical activity.

AB - LS 4477 and LS 4559, two of a series of N-acyl-aminoalkyl phenyl ethers, are rationally designed compounds based on the tubulin binder estramustine. This study investigated their mechanism of action and compared their effectiveness in relation to estramustine in vitro against a panel of human and murine cell lines and in vivo against two murine colon tumour models (MAC). At biologically relevant concentrations, LS 4477 and LS 4559 caused a 59.9 and 56% reduction in tubulin assembly, respectively, compared with a 28.4% reduction in tubulin assembly by estramustine. The analogues were approximately 100 times more potent in chemosensitivity tests in vitro than the parent compound. Both analogues were orally active against the MAC 15A murine tumour model, to a greater extent than estramustine, producing significant growth delays (P<0.01). Significant activity was also shown against the slower growing MAC 26 tumour for LS 4577 (the soluble pro-drug of LS 4559). The results presented in this study suggest these compounds warrant further development with a view to assessing their clinical activity.

KW - Animals

KW - Antineoplastic Agents, Alkylating/therapeutic use

KW - Binding, Competitive

KW - Colchicine/metabolism

KW - Colonic Neoplasms/drug therapy

KW - Dose-Response Relationship, Drug

KW - Drug Screening Assays, Antitumor

KW - Estramustine/analogs & derivatives

KW - Inhibitory Concentration 50

KW - Male

KW - Mice

KW - Microtubules/metabolism

KW - Prodrugs

KW - Swine

KW - Tubulin/metabolism

KW - Tubulin Modulators

KW - Tumor Cells, Cultured

U2 - 10.1016/S0959-8049(01)00341-0

DO - 10.1016/S0959-8049(01)00341-0

M3 - Article

VL - 38

SP - 194

EP - 204

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

IS - 1

ER -