Characterization of a Novel Prostate-Specific Antigen–Activated Peptide-Doxorubicin Conjugate in Patients With Prostate Cancer

DiPaola, Robert S.; Rinehart, John J.; Nemunaitis, John; Ebbinghaus, S.; Rubin, Eric H.; Capanna, Terry; Ciardella, Marie; Doyle-Lindrud, Susan; Goodwin, Susan; Fontaine, Michelle; Adams, Ned; Williams, A. S.; Schwartz, Michael; Winchell, Greg; Wickersham, Karen E; Deutsch, Paul; Yao, Siu-Long

doi:10.1200/jco.2002.07.001

Cited by 67 publications

(42 citation statements)

References 10 publications

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“…The first human trial with L-377,202 were recently completed and suggest that some of the improvements observed in mice will be translated to humans (42). In the case of MMP-activated prodrugs, this issue is particularly difficult to address because mouse tumors are poor models for human tumors with respect to MMP expression and activity.…”

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity

Albright

Graciani

Han

et al. 2005

Molecular Cancer Therapeutics

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Matrix metalloproteinase (MMP) -activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals,

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Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity

Albright

Graciani

Han

et al. 2005

Molecular Cancer Therapeutics

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“…These include proteins containing anthrax toxin fused to sequences cleaved specifically by uPA [123] or an-thracycline non-toxic pro-drugs that can be converted to an active parent drug by uPA [123], plasmin [124], or other serine proteinase such as prostate-specific antigen [125,126].…”

Section: Exploitation Of Proteolytic Activitymentioning

confidence: 99%

Role of plasminogen activator-plasmin system in tumor angiogenesis

Rakic¹,

Maillard²,

Jost³

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

118

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New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications.

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“…At the recommended dose of 225 mg/m 2 , equivalent to 90 mg of DOX/m 2 on a molar basis, two patients had a greater than 75% decline in PSA. A preferential delivery of DOX to PSA-positive tumor cells was not measured, but toxicity data indicated that it was possible to safely deliver about 1.5-fold more anthracycline compared with the conventional formulation on a molar basis (DiPaola et al, 2002).…”

mentioning

confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

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Characterization of a Novel Prostate-Specific Antigen–Activated Peptide-Doxorubicin Conjugate in Patients With Prostate Cancer

Abstract: This is the first study of selective drug delivery in humans using a novel PSA-activated agent. L-377202 was cleaved to produce detectable levels of the active metabolites Leu-Dox and Dox. L-377202 was well tolerated and established a safe dose level for further study.

Cited by 67 publications

References 10 publications

Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity

Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity

Role of plasminogen activator-plasmin system in tumor angiogenesis

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

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