Injection of Encapsulated Cells Producing an Ifosfamide‐Activating Cytochrome P450 for Targeted Chemotherapy to Pancreatic Tumors

Abstract

The prognosis of pancreatic cancer is poor, and current medical treatment is mostly ineffective. The aim of this study was to design a new treatment modality in an animal model system. We describe here a novel treatment strategy employing a mouse model system for pancreatic carcinoma. Embryonal kidney epithelial cells were genetically modified to express the cytochrome P450 subenzyme 2B1 under the control of a cytomegalovirus (CMV) immediate early promoter. This CYP2B1 gene converts ifosfamide to its active cytotoxic compounds, phosphoramide mustard, which alkylates DNA, and acrolein, which alkylates proteins. The cells were then encapsulated in a cellulose sulphate formulation and implanted into preestablished tumors derived from a human pancreatic tumor cell line. Intraperitoneal administration of low-dose ifosfamide to tumor bearing mice that received the encapsulated cells results in partial or even complete tumor ablation. Such an in situ chemotherapy strategy utilizing genetically modified cells in an immunoprotected environment may prove useful for solid tumor therapy in man.

Preparation of mammalian cell‐enclosing subsieve‐sized capsules (<100 μm) in a coflowing stream

“…In this study, a 2.0 wt% sodium alginate aqueous solution was used as a model of the viscous polymer solutions that have been used for mammalian cell encapsulation (Aomatsu et al, 2000;Cruise et al, 1998;Joki et al, 2001;Lim and Sun, 1980;Muller et al, 1999). We investigated nongelated droplets and confirmed the effectiveness of the coflowing breakup technique for the preparation of mammalian cellenclosing subsieve-sized monodisperse capsules.…”

“…These microcapsules had diameters of several hundred micrometers to enclose the islets that were 50-300 Am in diameter microencapsulation has been progressed based on techniques developed for islet-enclosing bioartificial pancreas (Chang et al, 1999;Orive et al, 2003;Sakai et al, 2002;Uludag et al,2000). Even for the encapsulation of single cells of less than 30 Am in diameter, microcapsules with diameters in the range of several hundred micrometers to millimeters have been used (Joki et al, 2001;Muller et al, 1999;Read et al, 2001).…”

“…A variety of polymer types, thermosensitive (Aomatsu et al, 2000), photosensitive (Cruise et al, 1998), and ioniccrosslinkable (Joki et al, 2001;Lim and Sun, 1980;Muller et al, 1999), have been used for mammalian cell encapsulation. All these solutions are viscous.…”

Targeting the CYP2B1/Cyclophosphamide Suicide System to Fibroblast Growth Factor Receptors Results in a Potent Antitumoral Response in Pancreatic Cancer Models

“…Interestingly, it has also been shown to be a promising therapeutic approach for pancreatic cancer both in mouse models and in clinical studies (Lohr et al, 1998;Muller et al, 1999;Lohr et al, 2001;Carrio et al, 2002). CPA and ifosfamide are alkylating prodrugs that covalently cross-link DNA in a cell cycleindependent manner, triggering apoptotic cell death in the case of CPA (Schwartz and Waxman, 2001), and either apoptosis or necrosis in the case of ifosfamide Schwartz and Waxman, 2001).…”

A multiprong approach to cancer gene therapy by coencapsulated cells

“…The pioneering work involved the encapsulation of cells expressing cytochrome P450 enzymes for converting a benign prodrug (ifosfamide) into a toxic metabolite for the treatment of pancreatic cancer. [5][6][7][8] Such encapsulated cells implanted close to the tumor site provided an alternate source of cytochrome P450 activity (the liver being the primary source). This strategy was to overcome limitations such as high toxicity and systemic dilution experienced with the bolus injection of the prodrug.…”