Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma

Löhr, Matthias; Hoffmeyer, Anne; Kröger, Jürgen; Freund, Mathias; Hain, Johannes; Holle, A.; Karle, Peter; Knöfel, Wolfram T; Liebe, Stefan; Müller, Petra; Nizze, H; Renner, Matthias; Saller, Robert; Wagner, Thomas; Hauenstein, Karlheinz; Günzburg, Walter H.; Salmons, Brian

doi:10.1016/s0140-6736(00)04749-8

Cited by 194 publications

(113 citation statements)

References 5 publications

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“…This general strategy may be implemented in a variety of ways, including using other slow release polymers that may be better optimized for small hydrophilic drugs such as CPA 40 or may be more suitable for clinical studies, or by localized instillation of prodrug to the tumor vasculature, as exemplified by preclinical and clinical studies of P450 prodrug gene therapy in pancreatic cancer. 21,47 Abbreviations AUC, area under the curve of drug concentration Â time; BW, body weight; C max , maximum concentration; CPA, cyclophosphamide; DMEM, Delbecco's modified Eagle's medium; F127, Pluronic F127 or poloxamer 407 block copolymer; FBS, fetal bovine serum; IFA, ifosfamide.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Chen

Jounaïdi

et al. 2007

Cancer Gene Ther

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The therapeutic utility of cytochrome P450-based enzyme prodrug therapy is well established by preclinical studies and in initial clinical trials. The underlying premise of this gene therapy is that intratumoral P450 expression leads to in situ activation of anticancer P450 prodrugs, such as cyclophosphamide (CPA), with intratumoral accumulation of its activated 4-OH metabolite. In mice bearing 9L gliosarcomas expressing the CPA 4-hydroxylase P450 2B6, enhanced tumor apoptosis was observed 48 h after CPA treatment; however, intratumoral 4-OH-CPA levels were indistinguishable from those of P450-deficient tumors, indicating that the bulk of activated CPA is derived from hepatic metabolism. In contrast, in 9L tumors expressing P450 2B11, a low K m CPA 4-hydroxylase, intratumoral 4-OH-CPA levels were higher than in blood, liver and P450-deficient tumors. Intratumoral 4-OH-CPA increased dose-dependently, without saturation at 140 mg kg À1 CPA, suggesting restricted tumor cell permeation of the parent drug. To circumvent this problem, CPA was administered by direct intratumoral injection, which increased the maximum concentration and area under the curve of drug concentration Â time (AUC) of intratumoral 4-OH-CPA by 1.8-and 2.7-fold, respectively. An overall 3.9-fold increase in intratumoral 4-OH-CPA AUC, and in antitumor activity, was obtained when CPA release to systemic circulation was delayed using the slow-release polymer poloxamer 407 as vehicle for intratumoral CPA delivery. These findings highlight the advantage of gene therapy strategies that combine low K m P450 prodrug activation enzymes with slow, localized release of P450 prodrug substrates.

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Section: Discussionmentioning

confidence: 99%

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Chen

Jounaïdi

et al. 2007

Cancer Gene Ther

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“…48 CYPbased GDEPT has also showed initial promising results in treating pancreatic cancer, in phase I clinical trials using CYP2B1 and ifosfamide. 28 At this stage improved results in gene therapy depend on more efficient delivery systems; however, due to the heterogeneous nature of tumor cells correct molecular characterization of tumors is necessary. Strategies have to be elaborated that can overcome to some extent this heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

“…Other delivery methods reported include retroviral constructs, 26 oncolytic vectors 13,27 and direct implantation of encapsulated CYP-engineered cells. 28,29 However, the ability of adenoviral vectors to infect both dividing and nondividing cells increases the proportion of infected cells. Since adenoviral vectors do not integrate into the host chromosomes, there is no risk of integration and mutagenesis of infected host tissue.…”

mentioning

confidence: 99%

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

Tychopoulos

Corcos

Genne³

et al. 2005

Cancer Gene Ther

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Virus-directed enzyme prodrug therapy (VDEPT) is an emerging strategy against cancer. Our approach is a P450-based VDEPT that consists of using cyclophosphamide (CPA) as a prodrug and a Cytochrome P450 2B6/NADPH cytochrome P450 reductase fusion protein (CYP2B6/RED) as a prodrug-activating enzyme. Due to the heterogenous expression of proteins in tumor cells, basal reductase activity may not be sufficient to supply CYP2B6 with electrons, the fusion protein should enable the expression of both proteins at high levels in tumor cells. CYP/RED fusion proteins have never been previously expressed in mammalian cells, to enable expression the fusion protein was cloned into an adenoviral vector and subsequently several pulmonary tumor cell lines were infected. The CYP2B6/RED fusion protein was detected by Western blot, its mRNA by Northern blot, and its heme incorporation into an active form by spectral analysis. Infection with the fusion gene increased RED activity in microsomes by a factor of 3 compared to the control. After infection and treatment with CPA, in cell lines with low endogenous RED, the fusion protein mediated significantly higher CPA-induced cytotoxicity compared to cells expressing solely CYP2B6. In conclusion, the fusion protein is functional for VDEPT by providing one protein for higher levels of CPA metabolism. Cancer Gene Therapy (2005) Keywords: VDEPT; P450-based gene therapy; cyclophosphamide; lung cancer G ene-directed enzyme prodrug therapy (GDEPT) 1,2 is an emerging strategy used to improve the selectivity of cancer chemotherapy. This is accomplished through tumor-specific activation of noncytotoxic prodrugs to active drugs by drug-metabolizing enzymes. The general scheme consists of transfection of tumor cells with an enzyme responsible for the bioactivation of a noncytotoxic prodrug and treatment with the prodrug: only cells expressing the transfected drug-metabolizing enzyme can metabolize the prodrug into cytotoxic metabolites, leading to cell death. The use of viral vectors for transgene introduction is more specifically referred to as virusdirected enzyme prodrug therapy (VDEPT). Following promising early results of a P450-based GDEPT strategy, 3 using the rat 9L gliosarcoma cell line, cyclophosphamide (CPA) as a prodrug and CYP2B1 as the prodrug activating enzyme, our approach was to improve the strategy by activating CPA with cytochrome P450 2B6 (CYP2B6) 4,5 or a CYP2B6/NADPH cytochrome P450 reductase (RED) fusion protein in order to avoid the frequent problem of low RED expression in tumor cells. This constructed protein is the fusion of two human proteins namely CYP2B6 and the human RED resulting in a single protein able to transfer electrons from NADPH right through to the heme moiety of the protein to enable metabolism of CYP2B6 substrates. In order to achieve high levels of expression in mammalian cells, the proteins were cloned into adenoviral vectors by homologous recombination.CPA belongs to the oxazaphosphorine class of molecules 6,7 and remains a widely used cytotoxic agent f...

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“…[2][3][4][5] There are several reports that have demonstrated the effectiveness of some targeted strategies involving monoclonal antibodies or immunotoxins to treat pancreatic cancer. 3,42 These approaches were limited because expression of the target antigens was insufficient to deliver targeting agents in sufficient quantity to eliminate all cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although many approaches are employed to treat this malignancy including surgery and chemotherapy, median survival following diagnosis is only 6 months, which has not improved in the past 30 years. [2][3][4][5] An effective new approach against this disease is desperately needed.…”

Section: Introductionmentioning

confidence: 99%

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Kawakami

Husain

et al. 2003

Gene Ther

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Interleukin-13 receptor (IL-13R) a2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ra2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ra2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ra2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ra2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.

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Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma

Cited by 194 publications

References 5 publications

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

Enhancement of intratumoral cyclophosphamide pharmacokinetics and antitumor activity in a P450 2B11-based cancer gene therapy model

A virus-directed enzyme prodrug therapy (VDEPT) strategy for lung cancer using a CYP2B6/NADPH-cytochrome P450 reductase fusion protein

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

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