INHIBITION OF ESTRONE SULFATASE ACTIVITY BY ESTRONE-3-METHYLTHIOPHOSPHONATE - A POTENTIAL THERAPEUTIC AGENT IN BREAST-CANCER

L DUNCAN, A PUROHIT, N M HOWARTH, B V L POTTER, M J REED

Research output: Contribution to journalArticle

Abstract

Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (EIS) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nm and 10 muM, inhibited estrone sulfatase activity by 52 and >98%, respectively. The apparent K(m) and V(max) for E1S were 4.8 muM and 148 pmol/min/mg for placental and 16.9 muM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the K(i) values for placental and tumor preparations being 14.6 and 32.8 muM, respectively. A comparison of the metabolism of [H-3]E1S and [H-3]E1-3-MTP by human placenta or rat liver revealed that, whereas 50-60% of [H-3]E1S was converted to [H-3]estrone, <3% of [H-3]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

Original languageEnglish
Pages (from-to)298-303
Number of pages6
JournalCancer Research
Volume53
Issue number2
Publication statusPublished - 15 Jan 1993

Cite this

@article{95dcb6f3e77c4b74b7c9dc9104a193f6,
title = "INHIBITION OF ESTRONE SULFATASE ACTIVITY BY ESTRONE-3-METHYLTHIOPHOSPHONATE - A POTENTIAL THERAPEUTIC AGENT IN BREAST-CANCER",
abstract = "Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (EIS) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nm and 10 muM, inhibited estrone sulfatase activity by 52 and >98{\%}, respectively. The apparent K(m) and V(max) for E1S were 4.8 muM and 148 pmol/min/mg for placental and 16.9 muM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the K(i) values for placental and tumor preparations being 14.6 and 32.8 muM, respectively. A comparison of the metabolism of [H-3]E1S and [H-3]E1-3-MTP by human placenta or rat liver revealed that, whereas 50-60{\%} of [H-3]E1S was converted to [H-3]estrone, <3{\%} of [H-3]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.",
author = "L DUNCAN and A PUROHIT and HOWARTH, {N M} and POTTER, {B V L} and REED, {M J}",
year = "1993",
month = "1",
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language = "English",
volume = "53",
pages = "298--303",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
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INHIBITION OF ESTRONE SULFATASE ACTIVITY BY ESTRONE-3-METHYLTHIOPHOSPHONATE - A POTENTIAL THERAPEUTIC AGENT IN BREAST-CANCER. / DUNCAN, L ; PUROHIT, A ; HOWARTH, N M ; POTTER, B V L ; REED, M J .

In: Cancer Research, Vol. 53, No. 2, 15.01.1993, p. 298-303.

Research output: Contribution to journalArticle

TY - JOUR

T1 - INHIBITION OF ESTRONE SULFATASE ACTIVITY BY ESTRONE-3-METHYLTHIOPHOSPHONATE - A POTENTIAL THERAPEUTIC AGENT IN BREAST-CANCER

AU - DUNCAN, L

AU - PUROHIT, A

AU - HOWARTH, N M

AU - POTTER, B V L

AU - REED, M J

PY - 1993/1/15

Y1 - 1993/1/15

N2 - Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (EIS) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nm and 10 muM, inhibited estrone sulfatase activity by 52 and >98%, respectively. The apparent K(m) and V(max) for E1S were 4.8 muM and 148 pmol/min/mg for placental and 16.9 muM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the K(i) values for placental and tumor preparations being 14.6 and 32.8 muM, respectively. A comparison of the metabolism of [H-3]E1S and [H-3]E1-3-MTP by human placenta or rat liver revealed that, whereas 50-60% of [H-3]E1S was converted to [H-3]estrone, <3% of [H-3]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

AB - Many breast tumors are hormone dependent, and there is evidence that hydrolysis of estrone sulfate (EIS) to estrone, by estrone sulfatase, is an important source of the estrogen which is found in tumors. In this study, we have developed a novel pathway for the synthesis of estrone-3-methylthiophosphonate (E1-3-MTP) and examined its ability to inhibit estrone sulfatase activity in MCF-7 breast cancer cells and human placental and breast tumor preparations. In MCF-7 breast cancer cells, E1-3-MTP, 100 nm and 10 muM, inhibited estrone sulfatase activity by 52 and >98%, respectively. The apparent K(m) and V(max) for E1S were 4.8 muM and 148 pmol/min/mg for placental and 16.9 muM and 38 pmol/min/mg for breast tumor preparations. Kinetic studies revealed that E1-3-MTP inhibited estrone sulfatase in a competitive manner with the K(i) values for placental and tumor preparations being 14.6 and 32.8 muM, respectively. A comparison of the metabolism of [H-3]E1S and [H-3]E1-3-MTP by human placenta or rat liver revealed that, whereas 50-60% of [H-3]E1S was converted to [H-3]estrone, <3% of [H-3]E1-3-MTP was hydrolyzed. The development of an efficient inhibitor of estrone sulfatase, which is resistant to metabolism, will allow the importance of the estrone sulfatase pathway of estrogen formation in breast tumors to be assessed and such an inhibitor may have considerable potential as a therapeutic agent.

M3 - Article

VL - 53

SP - 298

EP - 303

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 2

ER -