Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen

Samuel R. Denmeade, Attila Nagy, Jin Gao, Hans Lilja, Andrew V Schally, John T. Isaacs

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

New approaches to target cytotoxic therapy specifically to metastatic prostate cancer sites are urgently needed. As such an approach, an inactive prodrug was synthesized by coupling the primary amine of doxorubicin to the COOH-terminal carboxyl of a seven-amino acid peptide carrier (i.e., Mu-His- Ser-Ser-Lys-Leu-Gln-Leu). The seven-amino acid peptide was documented to be hydrolyzable specifically by the serine protease prostate-specific antigen (PSA) to liberate the active cytotoxin L-leucyl-doxorubicin. Primary cultures of PC-82 human prostate cancer cells secreted high levels of enzymatically active PSA (i.e., 70 ± 5 ng of enzymatically active PSA/106 cells/24 h), whereas LNCaP human prostate cancer ells produced lower levels of enzymatically active PSA (i.e., 2.3 ± 1 ng/106 cells/24 h). LNCaP cells, however, secreted sufficient amounts of enzymatically active PSA to activate the doxorubicin prodrug to a cytotoxic form in vitro. The specificity of the cytotoxic response to the prodrug was demonstrated by the fact that 70 nM of the prodrug killed 50% of the PSA-producing LNCaP cells, whereas doses as high as 1 ♂ had no cytotoxic effect on PSA-nonproducing TSU human prostate cancer cells in vitro.

Original languageEnglish
Pages (from-to)2537-2540
Number of pages4
JournalCancer Research
Volume58
Issue number12
StatePublished - Jun 15 1998
Externally publishedYes

Fingerprint

Prodrugs
Prostate-Specific Antigen
Doxorubicin
Peptides
Prostatic Neoplasms
Amino Acids
Cytotoxins
Serine Proteases
Amines

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Denmeade, S. R., Nagy, A., Gao, J., Lilja, H., Schally, A. V., & Isaacs, J. T. (1998). Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen. Cancer Research, 58(12), 2537-2540.

Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen. / Denmeade, Samuel R.; Nagy, Attila; Gao, Jin; Lilja, Hans; Schally, Andrew V; Isaacs, John T.

In: Cancer Research, Vol. 58, No. 12, 15.06.1998, p. 2537-2540.

Research output: Contribution to journalArticle

Denmeade, SR, Nagy, A, Gao, J, Lilja, H, Schally, AV & Isaacs, JT 1998, 'Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen', Cancer Research, vol. 58, no. 12, pp. 2537-2540.
Denmeade SR, Nagy A, Gao J, Lilja H, Schally AV, Isaacs JT. Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen. Cancer Research. 1998 Jun 15;58(12):2537-2540.
Denmeade, Samuel R. ; Nagy, Attila ; Gao, Jin ; Lilja, Hans ; Schally, Andrew V ; Isaacs, John T. / Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen. In: Cancer Research. 1998 ; Vol. 58, No. 12. pp. 2537-2540.
@article{d44aadecbe6f4fdb8ccfc1c76172216c,
title = "Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen",
abstract = "New approaches to target cytotoxic therapy specifically to metastatic prostate cancer sites are urgently needed. As such an approach, an inactive prodrug was synthesized by coupling the primary amine of doxorubicin to the COOH-terminal carboxyl of a seven-amino acid peptide carrier (i.e., Mu-His- Ser-Ser-Lys-Leu-Gln-Leu). The seven-amino acid peptide was documented to be hydrolyzable specifically by the serine protease prostate-specific antigen (PSA) to liberate the active cytotoxin L-leucyl-doxorubicin. Primary cultures of PC-82 human prostate cancer cells secreted high levels of enzymatically active PSA (i.e., 70 ± 5 ng of enzymatically active PSA/106 cells/24 h), whereas LNCaP human prostate cancer ells produced lower levels of enzymatically active PSA (i.e., 2.3 ± 1 ng/106 cells/24 h). LNCaP cells, however, secreted sufficient amounts of enzymatically active PSA to activate the doxorubicin prodrug to a cytotoxic form in vitro. The specificity of the cytotoxic response to the prodrug was demonstrated by the fact that 70 nM of the prodrug killed 50{\%} of the PSA-producing LNCaP cells, whereas doses as high as 1 ♂ had no cytotoxic effect on PSA-nonproducing TSU human prostate cancer cells in vitro.",
author = "Denmeade, {Samuel R.} and Attila Nagy and Jin Gao and Hans Lilja and Schally, {Andrew V} and Isaacs, {John T.}",
year = "1998",
month = "6",
day = "15",
language = "English",
volume = "58",
pages = "2537--2540",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen

AU - Denmeade, Samuel R.

AU - Nagy, Attila

AU - Gao, Jin

AU - Lilja, Hans

AU - Schally, Andrew V

AU - Isaacs, John T.

PY - 1998/6/15

Y1 - 1998/6/15

N2 - New approaches to target cytotoxic therapy specifically to metastatic prostate cancer sites are urgently needed. As such an approach, an inactive prodrug was synthesized by coupling the primary amine of doxorubicin to the COOH-terminal carboxyl of a seven-amino acid peptide carrier (i.e., Mu-His- Ser-Ser-Lys-Leu-Gln-Leu). The seven-amino acid peptide was documented to be hydrolyzable specifically by the serine protease prostate-specific antigen (PSA) to liberate the active cytotoxin L-leucyl-doxorubicin. Primary cultures of PC-82 human prostate cancer cells secreted high levels of enzymatically active PSA (i.e., 70 ± 5 ng of enzymatically active PSA/106 cells/24 h), whereas LNCaP human prostate cancer ells produced lower levels of enzymatically active PSA (i.e., 2.3 ± 1 ng/106 cells/24 h). LNCaP cells, however, secreted sufficient amounts of enzymatically active PSA to activate the doxorubicin prodrug to a cytotoxic form in vitro. The specificity of the cytotoxic response to the prodrug was demonstrated by the fact that 70 nM of the prodrug killed 50% of the PSA-producing LNCaP cells, whereas doses as high as 1 ♂ had no cytotoxic effect on PSA-nonproducing TSU human prostate cancer cells in vitro.

AB - New approaches to target cytotoxic therapy specifically to metastatic prostate cancer sites are urgently needed. As such an approach, an inactive prodrug was synthesized by coupling the primary amine of doxorubicin to the COOH-terminal carboxyl of a seven-amino acid peptide carrier (i.e., Mu-His- Ser-Ser-Lys-Leu-Gln-Leu). The seven-amino acid peptide was documented to be hydrolyzable specifically by the serine protease prostate-specific antigen (PSA) to liberate the active cytotoxin L-leucyl-doxorubicin. Primary cultures of PC-82 human prostate cancer cells secreted high levels of enzymatically active PSA (i.e., 70 ± 5 ng of enzymatically active PSA/106 cells/24 h), whereas LNCaP human prostate cancer ells produced lower levels of enzymatically active PSA (i.e., 2.3 ± 1 ng/106 cells/24 h). LNCaP cells, however, secreted sufficient amounts of enzymatically active PSA to activate the doxorubicin prodrug to a cytotoxic form in vitro. The specificity of the cytotoxic response to the prodrug was demonstrated by the fact that 70 nM of the prodrug killed 50% of the PSA-producing LNCaP cells, whereas doses as high as 1 ♂ had no cytotoxic effect on PSA-nonproducing TSU human prostate cancer cells in vitro.

UR - http://www.scopus.com/inward/record.url?scp=0032526152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032526152&partnerID=8YFLogxK

M3 - Article

VL - 58

SP - 2537

EP - 2540

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 12

ER -