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

Denmeade, Samuel R. ; Nagy, Attila ; Gao, Jin ; Lilja, Hans LU orcid ; Schally, Andrew V. and Isaacs, John T. (1998) In Cancer Research 58(12). p.2537-2540
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... (More)

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.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
58
issue
12
pages
2537 - 2540
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:0032526152
  • pmid:9635575
ISSN
0008-5472
language
English
LU publication?
yes
id
7ed68795-2267-43d7-9099-2ebcc3457f37
alternative location
https://aacrjournals.org/cancerres/article/58/12/2537/504219/Enzymatic-Activation-of-a-Doxorubicin-Peptide
date added to LUP
2022-12-06 15:56:32
date last changed
2024-02-18 10:25:28
@article{7ed68795-2267-43d7-9099-2ebcc3457f37,
  abstract     = {{<p>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/10<sup>6</sup> cells/24 h), whereas LNCaP human prostate cancer ells produced lower levels of enzymatically active PSA (i.e., 2.3 ± 1 ng/10<sup>6</sup> 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.</p>}},
  author       = {{Denmeade, Samuel R. and Nagy, Attila and Gao, Jin and Lilja, Hans and Schally, Andrew V. and Isaacs, John T.}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{12}},
  pages        = {{2537--2540}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{Enzymatic activation of a doxorubicin-peptide prodrug by prostate- specific antigen}},
  url          = {{https://aacrjournals.org/cancerres/article/58/12/2537/504219/Enzymatic-Activation-of-a-Doxorubicin-Peptide}},
  volume       = {{58}},
  year         = {{1998}},
}