A peptide–doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo

ABSTRACT We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the

peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However,

L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than

was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with

human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377,202. This

improvement in therapeutic index correlated with the selective localization of leucine–doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to

L-377,202. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to

this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy

now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact

customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TARGETED DELIVERY OF CYTOTOXIC PROTEINS TO PROSTATE CANCER VIA CONJUGATION TO SMALL MOLECULE UREA-BASED PSMA INHIBITORS Article Open

access 21 July 2021 A PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA)-TARGETED PRODRUG WITH A FAVORABLE IN VIVO TOXICITY PROFILE Article Open access 29 March 2021 DEVELOPMENT OF 177LU-SCFVD2B AS A

POTENTIAL IMMUNOTHERANOSTIC AGENT FOR TUMORS OVEREXPRESSING THE PROSTATE SPECIFIC MEMBRANE ANTIGEN Article Open access 09 June 2020 REFERENCES * Husain, M.H., Blumenstein, B., Eisenberger,

M. & Crawford, E.D. Southwest Oncology Group studies in hormone-refractory prostate cancer. _Semin. Oncol._ 23, 24–27 (1996). Google Scholar  * Lilja, H. A kallikrein-like serine

protease in prostatic fluid cleaves the predominant seminal vesicle protein. _J. Clin. Invest._ 76, 1899–1903 (1985). Article  CAS  Google Scholar  * Akiyama, K., Nakamura, T., Iwanaza, S.

& Hara, M. The chymotrypsin-like activity of human prostate specific antigen, g-seminoprotein. _FEBS LETTERS_ 235, 168–172 (1987)] Article  Google Scholar  * Yu, H. et al. Ectopic

production of prostate specific antigen by a breast tumor metastatic to the ovary. _J. Clin. Lab. Anal._ 8, 251–253 (1994) Article  CAS  Google Scholar  * Diamandis, E., Yu, H. &

Sutherland, D.J.A. Detection of prostate specific antigen immunoreactivity in breast tumors. _Breast Cancer Res. Tr._ 32, 301–310 (1994). Article  CAS  Google Scholar  * Yu, H., Diamandis,

E. & Sutherland, D.J.A. Immunoreactive prostate specific antigen levels in female and male breast tumors and its association with steroid hormone receptors and patient age. _Clin.

Biochem._ 27, 75–79 (1994). Article  CAS  Google Scholar  * Levesque, M., Yu, H., D'Costa, M. & Diamandis, E. . Prostate specific antigen expression by various tumors. _J. Clin.

Lab. Anal._ 9, 123–128 (1995). Article  CAS  Google Scholar  * Diamandis, E. New diagnostic applications and physiological functions of prostate specific antigen. _Scand. J. Clin. Lab.

Invest._ 55, 105–112 (1995). Article  Google Scholar  * Catalona, W.J., Smith, D.S., Ratliff, T.L., Dodds, K. M., Coplen, d.e., Yuan, J. J., Petros, J.A., & Andriole, G.L., Measurement

of Prostrate-specific antigen in serum as a screning test for Prostrae cancer. _New England Journal of Medicine_ 324, 1156(1991).] Article  CAS  Google Scholar  * Christensson, A., Laurell,

C. & Lilja. H. . Enzymatic activity of prostate specific antigen and its reactions with extracellular serine proteinase inhibitors. _Eur. J. Biochem._ 194, 755–763 (1990). Article  CAS 

Google Scholar  * Leinonen, J., Zhang. W. & Stenman, U. . Complex formation between psa isoenzymes and protease inhibitors. _J. Urol._ 155, 1099–1103 (1996). Article  CAS  Google Scholar

  * Otto, A., Bar, J. & Birkenmeier, G. Prostate specific antigen forms complexes with human a2-macroglobulin and binds to the a2-macroglobulin receptor/ldl receptor-related protein. _J.

Urol._ 159, 297–303 (1998). Article  CAS  Google Scholar  * Christensson, A. & Lilja, H. Complex formation between protein C inhibitor and prostate specific antigen in vitro and in

human semen. _Eur. J. Biochem._ 220, 45–53 (1994). Article  CAS  Google Scholar  * Wainstein, M.A. et al. CWR22: androgen-dependent xenograft model derived from a primary prostatic

carcinoma. _Cancer Res._ 54, 6049–6052 (1994). CAS  PubMed  Google Scholar  * Denmeade, S.R. et al. Enzymatic activation of a doxorubicin-peptide prodrug by prostate specific antigen.

_Cancer Res._ 58, 2537–2540 (1998). CAS  PubMed  Google Scholar  * Tan, C. et al. Daunorubicin, an antitumoral antibiotic in the treatment of neoplastic disease. Clinical evaluation with

special reference to childhood leukemia. _Cancer_ 20, 333–353 (1967). Article  CAS  Google Scholar  * Macrez, C. et al. Accidents cardiaques observes en cours des traitment par rubidomycine.

_Pathol. Biol._ 15, 949–953 (1967). CAS  PubMed  Google Scholar  * Johansen, P.B. . Doxorubicin pharmacokinetics after intravenous and intraperitoneal administration in the nude mouse.

Cancer Chemother. _Pharmacol._ 5, 267–270 (1981). CAS  Google Scholar  * Westfall, P.H. & Young, S.S. in _Resampling Based Multiple Testing_ (John Wiley & Sons, New York, 1993). pp

112–145 Google Scholar  * SAS Institute. _SAS/STAT Software: Changes and Enhancements Through Release 6.11_. (SAS Institute, Cary, North Carolina, 1996). * Dunnett, C.W. A multiple

comparison procedure for comparing several treatments with a control. _J. American Statistical Assoc._ 50, 1096–1121 (1955). Article  Google Scholar  * SAS Institute. _SAS/STAT User's

Guide Version 6_, 4th edn. Vol. 2 (SAS Institute, Cary, North Carolina, 1990). pp 891–996 Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Cancer Research, Merck Research

Laboratories, West Point, 19486, Pennsylvania, USA Deborah DeFeo-Jones, Trina Bolyar, Kathleen Haskell, David M. Kiefer, Karen Leander, Elizabeth McAvoy & Raymond E. Jones * Medicinal

Chemistry, Merck Research Laboratories, West Point, 19486, Pennsylvania, USA Victor M. Garsky, Dong-Mei Feng, Patricia Lumma, Jenny Wai, Roger Freidinger & Joel Huff * Drug Metabolism,

Merck Research Laboratories, West Point, 19486, Pennsylvania, USA Bradley K. Wong & Jiunn H. Lin * Vaccine Biometrics Research, Merck Research Laboratories, West Point, 19486,

Pennsylvania, USA Edith T. Senderak * Laboratory Animal Resources, Merck Research Laboratories, West Point, 19486, Pennsylvania, USA Sherri L. Motzel * Safety Assessment, Merck Research

Laboratories, West Point, 19486, Pennsylvania, USA Kevin Keenan & Matthew Van Zwieten * Dupont Pharmaceuticals, Experimental Station, Wilmington, 19880, Delaware, USA Allen Oliff Authors

* Deborah DeFeo-Jones View author publications You can also search for this author inPubMed Google Scholar * Victor M. Garsky View author publications You can also search for this author

inPubMed Google Scholar * Bradley K. Wong View author publications You can also search for this author inPubMed Google Scholar * Dong-Mei Feng View author publications You can also search

for this author inPubMed Google Scholar * Trina Bolyar View author publications You can also search for this author inPubMed Google Scholar * Kathleen Haskell View author publications You

can also search for this author inPubMed Google Scholar * David M. Kiefer View author publications You can also search for this author inPubMed Google Scholar * Karen Leander View author

publications You can also search for this author inPubMed Google Scholar * Elizabeth McAvoy View author publications You can also search for this author inPubMed Google Scholar * Patricia

Lumma View author publications You can also search for this author inPubMed Google Scholar * Jenny Wai View author publications You can also search for this author inPubMed Google Scholar *

Edith T. Senderak View author publications You can also search for this author inPubMed Google Scholar * Sherri L. Motzel View author publications You can also search for this author

inPubMed Google Scholar * Kevin Keenan View author publications You can also search for this author inPubMed Google Scholar * Matthew Van Zwieten View author publications You can also search

for this author inPubMed Google Scholar * Jiunn H. Lin View author publications You can also search for this author inPubMed Google Scholar * Roger Freidinger View author publications You

can also search for this author inPubMed Google Scholar * Joel Huff View author publications You can also search for this author inPubMed Google Scholar * Allen Oliff View author

publications You can also search for this author inPubMed Google Scholar * Raymond E. Jones View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to Raymond E. Jones. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE DeFeo-Jones, D., Garsky, V., Wong, B. _et al._ A

peptide–doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen _in vivo_. _Nat Med_ 6, 1248–1252

(2000). https://doi.org/10.1038/81351 Download citation * Received: 03 April 2000 * Accepted: 15 September 2000 * Issue Date: November 2000 * DOI: https://doi.org/10.1038/81351 SHARE THIS

ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard

Provided by the Springer Nature SharedIt content-sharing initiative