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

Defeo-Jones, Deborah; Garsky, Victor M.; Wong, Bradley K.; Feng, Da Hsuan; Bolyar, Trina; Haskell, Kathleen; Kiefer, David M.; Leander, Karen; McAvoy, Elizabeth; Lumma, Patricia K.; Wai, Jenny M.; Senderak, Edith T.; Motzel, Sherri L.; Keenan, Kevin P.; Zwieten, Matthew Van; Lin, Jiunn H.; Freidinger, Roger; Huff, Joel R.; Oliff, Allen; Jones, Raymond E.

doi:10.1038/81351

Cited by 146 publications

(127 citation statements)

References 15 publications

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“…23,24 A phase I study has been carried out with L-377,202 with 225 mg/m 2 being established as the MTD in this study that corresponds to 90 mg/m 2 doxorubicin equivalents.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] These doxorubicin derivatives include the peptide sequences MuHis-Ser-Ser-Lys-Leu-Gln-Leu-OH (Mu 5 morpholinocarbonyl) and N-glutaryl-(hydroxypropyl)-Ala-Ser-cyclohexylglycyl-Gln-SerLeu-OH (abbreviated L-377,202) bound to the amino position of doxorubicin. Both low-molecular weight prodrugs were designed to release N-(L-leucyl)doxorubicin after cleavage by PSA.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Graeser¹,

Chung

Esser³

et al. 2007

Intl Journal of Cancer

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The prostate-specific antigen (PSA) is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albuminbound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062-4066). In this work, we describe an albumin-binding prodrug, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO [EMC: e-Maleimidocaproic acid; DOXO 5 doxorubicin; X 5 amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water-solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA-positive tumors (LNCaP) demonstrated that the albumin-bound form of the prodrug was efficiently cleaved by PSA at the P 1 -P 0 1 scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was 100-fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 3 4 mg/kg caused significant weight loss and mortality (225%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 3 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (625%, **p 5 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (250%, SD 6 115%, *p 5 0.038). ' 2007 Wiley-Liss, Inc.Key words: doxorubicin; macromolecular prodrug; human serum albumin; PSA; orthotopic animal model; LNCaP; luciferase; in vivo bioluminescence Hormone refractory prostate cancer responds unfavorably to chemotherapy. The best results to date are achieved with Taxotere. 1 To improve prostate cancer therapy, tumor-specific delivery of anticancer agents to the primary tumor and metastases is a goal worth pursuing.For selectively releasing anticancer agents, the prostate-specific antigen (PSA) is especially attractive as a target protease because it is solely expressed in prostate tissue and prostate carcinoma in prostate cancer patients with high levels up to mg/g present in human prostate carcinoma. 2,3 PSA is a serine protease that belongs to the kallikrein gene family with chymotrypsin-like activity that is involved in the hydrolytic processing of semenogelins (cleavage of the semenal fluid proteins semenogelin I and II), which is required for liquefaction of seminal fluids. 2,3 Over...

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“…23,24 A phase I study has been carried out with L-377,202 with 225 mg/m 2 being established as the MTD in this study that corresponds to 90 mg/m 2 doxorubicin equivalents.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Graeser¹,

Chung

Esser³

et al. 2007

Intl Journal of Cancer

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“…Therefore, PSA is an attractive target of tissue-specific therapy. For example, a peptidedoxorubicin 'prodrug', which is cleaved and activated by PSA, selectively kills prostate tumour cells in vivo (DeFeo-Jones et al, 2000).…”

Section: Hormonal Therapy In Prostate Cancermentioning

confidence: 99%

Tissue-selective therapy of cancer

2003

Br J Cancer

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“…[7][8][9] These prodrugs were developed with the aim of reducing toxicity and improving both the efficacy and the selectivity of chemotherapeutic agents for treating hormone-refractory prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP)

Elsadek¹,

Graeser²,

Esser³

et al. 2010

Prostate Cancer Prostatic Dis

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PSA, which is overexpressed in prostate carcinoma, represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this study, we report on the in vivo antitumor efficacy of an efficacious albumin-binding prodrug of doxorubicin (PSA9) that incorporates p-aminobenzyloxycarbonyl (PABC) as a self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, which serves as a substrate for PSA. The prodrug is cleaved very efficiently by PSA releasing H-Ser-Leu-PABC-doxorubicin and subsequently doxorubicin in PSA-positive cell lysates and prostate tumor homogenates as the final cleavage product. PSA9 at 3 Â 6 mg kg À1 doxorubicin equivalents (intravenous) was compared with conventional doxorubicin at equitoxic doses (at 3 Â 3 mg kg À1 ; intravenous) in an orthotopic mouse model of prostate cancer using LNCaP lentiviral luciferase-neomycin cells transduced with luciferase. Whereas doxorubicin did not show any efficacy against the primary tumor or metastases, the prodrug reduced the primary tumor by 30-50% and circulating PSA levels, and in addition, showed a pronounced reduction in lung and bone metastases by B77% and B96%, respectively, and a positive trend regarding the activity against liver and lymph-node metastases compared with control and doxorubicin-treated animals. The incorporation of PABC as a self-immolative spacer together with a PSA substrate demonstrates superior antitumor effects over doxorubicin attributed to an efficient cleavage by PSA releasing doxorubicin as the final active agent in prostate tumor homogenates. Using this approach for developing effective prodrugs against prostate cancer, is worthy of further preclinical optimization.

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

Cited by 146 publications

References 15 publications

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Tissue-selective therapy of cancer

In vivo evaluation of a novel albumin-binding prodrug of doxorubicin in an orthotopic mouse model of prostate cancer (LNCaP)

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