Antitumor Activity of an Enzyme Prodrug Therapy Targeted to the Breast Tumor Vasculature

Rite, Brent D. Van; Krais, John J.; Cherry, Mohamad; Sikavitsas, Vassilios I.; Kurkjian, Carla; Harrison, Roger G.

doi:10.3109/07357907.2013.840383

Cited by 19 publications

(12 citation statements)

References 17 publications

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“…Cytotoxic efficacy of our FP systems on HAAE-1 cells has also been demonstrated previously in vitro, with cell killing ranging from 5-100% [23]–[25]. We have validated these in vitro methods for determining vascular targeting/cytotoxic efficacy via the successful transition of the MT-AV/SeMet system in vivo for mice with implanted MDA-MB-231 breast tumors [38]. …”

Section: Introductionsupporting

confidence: 55%

Targeted enzyme prodrug therapy for metastatic prostate cancer – a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase

2014

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BackgroundEnzyme prodrug therapy shows promise for the treatment of solid tumors, but current approaches lack effective/safe delivery strategies. To address this, we previously developed three enzyme-containing fusion proteins targeted via annexin V to phosphatidylserine exposed on the tumor vasculature and tumor cells, using the enzymes L-methioninase, purine nucleoside phosphorylase, or cytosine deaminase. In enzyme prodrug therapy, the fusion protein is allowed to bind to the tumor before a nontoxic drug precursor, a prodrug, is introduced. Upon interaction of the prodrug with the bound enzyme, an anticancer compound is formed, but only in the direct vicinity of the tumor, thereby mitigating the risk of side effects while creating high intratumoral drug concentrations. The applicability of these enzyme prodrug systems to treating prostate cancer has remained unexplored. Additionally, target availability may increase with the addition of low dose docetaxel treatment to the enzyme prodrug treatment, but this effect has not been previously investigated. To this end, we examined the binding strength and the cytotoxic efficacy (with and without docetaxel treatment) of these enzyme prodrug systems on the human prostate cancer cell line PC-3.ResultsAll three fusion proteins exhibited strong binding; dissociation constants were 0.572 nM for L-methioninase-annexin V (MT-AV), 0.406 nM for purine nucleoside phosphorylase-annexin V (PNP-AV), and 0.061 nM for cytosine deaminase-annexin V (CD-AV). MT-AV produced up to 99% cell death (p < 0.001) with limited cytotoxicity of the prodrug alone. PNP-AV with docetaxel created up to 78% cell death (p < 0.001) with no cytotoxicity of the prodrug alone. CD-AV with docetaxel displayed up to 60% cell death (p < 0.001) with no cytotoxicity of the prodrug alone. Docetaxel treatment created significant increases in cytotoxicity for PNP-AV and CD-AV.ConclusionsStrong binding of fusion proteins to the prostate cancer cells and effective cell killing suggest that the enzyme prodrug systems with MT-AV and PNP-AV may be effective treatment options. Additionally, low-dose docetaxel treatment was found to increase the cytotoxic effect of the annexin V-targeted therapeutics for the PNP-AV and CD-AV systems.

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Section: Introductionsupporting

confidence: 55%

Targeted enzyme prodrug therapy for metastatic prostate cancer – a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase

2014

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“…The key characteristics of targeted enzymes are their biodistribution and pharmacokinetic properties. These enzymes should exhibit a high uptake level at the tumor site, and should degrade rapidly in the blood and normal tissues, converting the prodrugs in a site-specific manner (2,3,24,25). Therefore, it is important to investigate the in vivo distribution and clearance mechanisms of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

Targeting assay of a fusion protein applied in enzyme prodrug therapy

2017

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Tumor growth and metastasis are dependent on angiogenesis. The overexpression of integrin αvβ3 on angiogenic vessels and on numerous malignant human tumor cells suggests that these labeled ligands of integrin are potentially suitable for molecular imaging and in targeted therapy of tumors. In previous studies, we added a β-lactamase variant with reduced immunogenicity to the cyclic peptide RGD4C, resulting in the fusion protein RGD4CβL, which is suitable for use in targeted enzyme prodrug therapy (TEPT), a promising treatment for tumors. The targeting of the aforementioned fusion protein serves an important role in TEPT. In the present study, RGD4CβL was labeled with 125I and the targeting effect on integrin-positive tumors was evaluated. The results demonstrated that the 125I-RGD4CβL protein exhibited high levels of accumulation at the tumor site and rapid renal clearance, which revealed the potency and efficiency of RGD4CβL in TEPT.

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“…The cytotoxic agent can be precisely released at tumor site which can avoid systemic toxicity, and can diffuse into adjacent cells making the non-antigen expressed tumor cells undergo treatment [4], which can further improve the treatment. The enzymes used in this strategy have relatively fixed relations with prodrugs, such as carboxypeptidase G2 and benzoic mustard [5], nitroreductase and CB1954 [6,7], l -methioninase and selenomethionine [8,9], cytosine deaminase and 5-fluorocytosine [9,10], β-lactamase and cephalosporin prodrugs [11,12]. In the previous study we constructed a conjugate (RGD4CβL) of RGD4C (ACDCRGDCFCG) and β-lactamase variant with low immunogenicity for use in the enzyme prodrug therapy, in which the RGD4C motif served as direct group for its specificity to α v β 3 integrin which is overexpressed on tumor cells and is usability for incorporation into proteins by recombinant technology [13,14,15], and studies showed the fusion protein not only retains catalytic activity of β-lactamase but has low immunogenicity and high stability [16,17].…”

Section: Introductionmentioning

confidence: 99%

A Fusion Protein of RGD4C and β-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy

Wang

Xiaoliang

Long

et al. 2015

IJMS

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Antibody directed enzyme prodrug therapy (ADEPT) utilizing β-lactamase is a promising treatment strategy to enhance the therapeutic effect and safety of cytotoxic agents. In this method, a conjugate (antibody-β-lactamase fusion protein) is employed to precisely activate nontoxic cephalosporin prodrugs at the tumor site. A major obstacle to the clinical translation of this method, however, is the low catalytic activity and high immunogenicity of the wild-type enzymes. To overcome this challenge, we fused a cyclic decapeptide (RGD4C) targeting to the integrin with a β-lactamase variant with reduced immunogenicity which retains acceptable catalytic activity for prodrug hydrolysis. Here, we made a further investigation on its targeting effect and pharmacokinetic properties, the results demonstrated that the fusion protein retains a targeting effect on integrin positive cells and has acceptable pharmacokinetic characteristics, which benefits its use in ADEPT.

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Antitumor Activity of an Enzyme Prodrug Therapy Targeted to the Breast Tumor Vasculature

Cited by 19 publications

References 17 publications

Targeted enzyme prodrug therapy for metastatic prostate cancer – a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase

Targeted enzyme prodrug therapy for metastatic prostate cancer – a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase

Targeting assay of a fusion protein applied in enzyme prodrug therapy

A Fusion Protein of RGD4C and β-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy

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