Enzyme-Prodrung Therapies of Cancer

Knox, Richard J.; Melton, Roger G.; Satchi, Ronit

doi:10.1201/9780203904671.ch33

Cited by 1 publication

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“…Clinically, combination chemotherapy is routinely used in an attempt to increase efficacy, bypass resistance, and minimize the peripheral toxicity that is often dose-limiting. The PDEPT concept was developed with the aim of further improving the tumor selectivity of polymer-drug conjugates ( 9) and also to circumvent some of the disadvantages of ADEPT (discussed in 9,16). A model combination of HPMA-co-MA-GG-cathepsin B and HPMAco-MA-GLFG-Dox demonstrated the practicality of the approach (9).…”

Section: Resultsmentioning

confidence: 99%

“…A wide variety of cytotoxic agents bearing NH 2 or OH groups can be used to create prodrugs. Cephalosporin derivatives of various mustards (12), taxol (13), and doxorubicin (14, 15) have already been described as low molecular weight prodrugs for the antibody-directed enzyme prodrug (ADEPT) approach (16). As β-L is not a mammalian enzyme, it should display minimal interference from mammalian inhibitors, physiological enzyme substrates, and competing endogenous enzyme systems.…”

Section: Introductionmentioning

confidence: 99%

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PDEPT: Polymer-Directed Enzyme Prodrug Therapy. 2. HPMA Copolymer-β-lactamase and HPMA Copolymer-C-Dox as a Model Combination

et al. 2003

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Polymer-directed enzyme prodrug therapy (PDEPT) is a novel two-step antitumor approach that uses a combination of a polymeric prodrug and polymer-enzyme conjugate to generate a cytotoxic drug rapidly and selectively at the tumor site. Previously we have shown that N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound cathepsin B can release doxorubicin intratumorally from an HPMA copolymer conjugate PK1. Here we describe for the first time the synthesis and biological characterization of a PDEPT model combination that uses an HPMA-copolymer-methacryloyl-glycine-glycine-cephalosporin-doxorubicin (HPMA-co-MA-GG-C-Dox) as the macromolecular prodrug and an HPMA copolymer conjugate containing the nonmammalian enzyme beta-lactamase (HPMA-co-MA-GG-beta-L) as the activating component. HPMA-co-MA-GG-C-Dox had a molecular weight of approximately 31 600 Da and a C-Dox content of 5.85 wt %. Whereas free beta-L has a molecular weight of 45 kDa, the HPMA-co-MA-GG-beta-L conjugate had a molecular weight in the range of 75-150 kDa, and following purification no free enzyme was detectable. Against the cephalosporin C or HPMA-co-MA-GG-C-Dox substrates, the HPMA-co-MA-GG-beta-L conjugate retained 70% and 80% of its activity, respectively. In vivo (125)I-labeled HPMA-co-MA-GG-beta-L showed prolonged plasma concentration and greater tumor targeting than (125)I-labeled beta-L due to the enhanced permeability and retention (EPR) effect. Moreover, administration of HPMA-co-MA-GG-C-Dox iv to mice bearing sc B16F10 melanoma followed after 5 h by HPMA-co-MA-GG-beta-L led to release of free Dox. The PDEPT combination caused a significant decrease in tumor growth (T/C = 132%) whereas neither free Dox nor HPMA-co-MA-GG-C-Dox alone displayed activity. The PDEPT combination displayed no toxicity at the doses used, so further evaluation of this approach to establish the maximum tolerated dose (MTD) is recommended.

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Section: Resultsmentioning

confidence: 99%