Seleetive delivery of cytotoxic compounds to cells by the LDL pathway

Raymond A. Firestone, Judith M. Pisano, J R Falck, Michael M. McPhaul, Monty Krieger

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Cancer celle need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

Original languageEnglish (US)
Pages (from-to)1037-1043
Number of pages7
JournalJournal of Medicinal Chemistry
Volume27
Issue number8
StatePublished - 1984

Fingerprint

LDL Lipoproteins
Cell Count
LDL Receptors
Bearings (structural)
Neoplasms
Apoproteins
VLDL Lipoproteins
Cholesterol Esters
Endocytosis
Lysosomes
Phospholipids
Toxicity
Cholesterol
Blood
Membranes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Firestone, R. A., Pisano, J. M., Falck, J. R., McPhaul, M. M., & Krieger, M. (1984). Seleetive delivery of cytotoxic compounds to cells by the LDL pathway. Journal of Medicinal Chemistry, 27(8), 1037-1043.

Seleetive delivery of cytotoxic compounds to cells by the LDL pathway. / Firestone, Raymond A.; Pisano, Judith M.; Falck, J R; McPhaul, Michael M.; Krieger, Monty.

In: Journal of Medicinal Chemistry, Vol. 27, No. 8, 1984, p. 1037-1043.

Research output: Contribution to journalArticle

Firestone, RA, Pisano, JM, Falck, JR, McPhaul, MM & Krieger, M 1984, 'Seleetive delivery of cytotoxic compounds to cells by the LDL pathway', Journal of Medicinal Chemistry, vol. 27, no. 8, pp. 1037-1043.
Firestone RA, Pisano JM, Falck JR, McPhaul MM, Krieger M. Seleetive delivery of cytotoxic compounds to cells by the LDL pathway. Journal of Medicinal Chemistry. 1984;27(8):1037-1043.
Firestone, Raymond A. ; Pisano, Judith M. ; Falck, J R ; McPhaul, Michael M. ; Krieger, Monty. / Seleetive delivery of cytotoxic compounds to cells by the LDL pathway. In: Journal of Medicinal Chemistry. 1984 ; Vol. 27, No. 8. pp. 1037-1043.
@article{611d563364824a039e86e7ff0c518f4b,
title = "Seleetive delivery of cytotoxic compounds to cells by the LDL pathway",
abstract = "Cancer celle need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.",
author = "Firestone, {Raymond A.} and Pisano, {Judith M.} and Falck, {J R} and McPhaul, {Michael M.} and Monty Krieger",
year = "1984",
language = "English (US)",
volume = "27",
pages = "1037--1043",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Seleetive delivery of cytotoxic compounds to cells by the LDL pathway

AU - Firestone, Raymond A.

AU - Pisano, Judith M.

AU - Falck, J R

AU - McPhaul, Michael M.

AU - Krieger, Monty

PY - 1984

Y1 - 1984

N2 - Cancer celle need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

AB - Cancer celle need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

UR - http://www.scopus.com/inward/record.url?scp=0021140661&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0021140661&partnerID=8YFLogxK

M3 - Article

VL - 27

SP - 1037

EP - 1043

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -