An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11

Wierdl, Monika; Tsurkan, Lyudmila; Hyatt, Janice L.; Edwards, Carol C.; Hatfield, M. Jason; Morton, Christopher L.; Houghton, Peter J.; Danks, Mary K.; Redinbo, Matthew R.; Potter, Philip M.

doi:10.1038/sj.cgt.7701112

Cited by 44 publications

(63 citation statements)

References 25 publications

(36 reference statements)

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“…If the immunogenic potential of the vector or the transgene prohibits clinical use, obvious alternative are to use 'empty vectors', to delete immunogenic sequences not required for protein function, or to 'humanize' immunogenic domains of non-human coding sequences, as has been reported for the rabbit CE that efficiently activates the prodrug irinotecan. 114 Until conditions are identified that permit unlimited expansion of clonal populations of autologous primary cells engineered to express a therapeutic of interest, wellcharacterized cell lines are most likely to have clinical utility.…”

Section: Immunogenicitymentioning

confidence: 99%

Stem and progenitor cell-mediated tumor selective gene therapy

2008

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The poor prognosis for patients with aggressive or metastatic tumors and the toxic side effects of currently available treatments necessitate the development of more effective tumor-selective therapies. Stem/progenitor cells display inherent tumor-tropic properties that can be exploited for targeted delivery of anticancer genes to invasive and metastatic tumors. Therapeutic genes that have been inserted into stem cells and delivered to tumors with high selectivity include prodrug-activating enzymes (cytosine deaminase, carboxylesterase, thymidine kinase), interleukins (IL-2, IL-4, IL-12, IL-23), interferon-b, apoptosis-promoting genes (tumor necrosis factor-related apoptosis-inducing ligand) and metalloproteinases (PEX). We and others have demonstrated that neural and mesenchymal stem cells can deliver therapeutic genes to elicit a significant antitumor response in animal models of intracranial glioma, medulloblastoma, melanoma brain metastasis, disseminated neuroblastoma and breast cancer lung metastasis. Most studies reported reduction in tumor volume (up to 90%) and increased survival of tumor-bearing animals. Complete cures have also been achieved (90% disease-free survival for 41 year of mice bearing disseminated neuroblastoma tumors). As we learn more about the biology of stem cells and the molecular mechanisms that mediate their tumor-tropism and we identify efficacious gene products for specific tumor types, the clinical utility of cell-based delivery strategies becomes increasingly evident.

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Section: Immunogenicitymentioning

confidence: 99%

Stem and progenitor cell-mediated tumor selective gene therapy

2008

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“…Control nontransduced HB1.F3.CD cells were cultured under identical conditions. Adenoviral stock for each virus type, AdrCE [20] or AdhCE1m6 [24], was diluted in media and added to cells to give a final multiplicity of infection (MOI) of 20. NSCs were incubated for 18 -24 hours, washed with phosphate-buffered saline (PBS), trypsinized, and resuspended in fresh culture medium.…”

Section: Neural Stem Cell Culturementioning

confidence: 99%

Neural Stem Cell-Mediated Delivery of Irinotecan-Activating Carboxylesterases to Glioma: Implications for Clinical Use

Metz

Gutova

Lacey

et al. 2013

Stem Cells Translational Medicine

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CPT-11 (irinotecan) has been investigated as a treatment for malignant brain tumors. However, limitations of CPT-11 therapy include low levels of the drug entering brain tumor sites and systemic toxicities associated with higher doses. Neural stem cells (NSCs) offer a novel way to overcome these obstacles because of their inherent tumor tropism and ability to cross the blood-brain barrier, which enables them to selectively target brain tumor sites. Carboxylesterases (CEs) are enzymes that can convert the prodrug CPT-11 (irinotecan) to its active metabolite SN-38, a potent topoisomerase I inhibitor. We have adenovirally transduced an established clonal human NSC line (HB1.F3.CD) to express a rabbit carboxylesterase (rCE) or a modified human CE (hCE1m6), which are more effective at converting CPT-11 to SN-38 than endogenous human CE. We hypothesized that NSC-mediated CE/CPT-11 therapy would allow tumor-localized production of SN-38 and significantly increase the therapeutic efficacy of irinotecan. Here, we report that transduced NSCs transiently expressed high levels of active CE enzymes, retained their tumor-tropic properties, and mediated an increase in the cytotoxicity of CPT-11 toward glioma cells. CE-expressing NSCs (NSC.CEs), whether administered intracranially or intravenously, delivered CE to orthotopic human glioma xenografts in mice. NSCdelivered CE catalyzed conversion of CPT-11 to SN-38 locally at tumor sites. These studies demonstrate the feasibility of NSC-mediated delivery of CE to glioma and lay the foundation for translational studies of this therapeutic paradigm to improve clinical outcome and quality of life in patients with malignant brain tumors. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:983-992

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“…Finally, tumorlocated expression of carboxylesterase, responsible for the catalytic hydrolysis of CPT-11 to SN-38, can sensitize tumor cells to CPT-11 in vitro and in vivo. 49,50 As carboxyesterases act on CPT-11 whereas bG acts on SN-38G, combined treatment with Ad.bG and Ad.carboxyesterase vectors may offer a rationale method to further enhance the antitumor efficacy of CPT-11.…”

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Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Huang

Prijovich

et al. 2011

Cancer Gene Ther

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CPT-11 is a clinically important prodrug that requires conversion into the active metabolite SN-38, a potent topoisomerase I poison, for antitumor activity. However, SN-38 is rapidly metabolized to the inactive SN-38 glucuronide (SN-38G) in the liver, which reduces the amount of SN-38 available for killing cancer cells. Here, we investigated if local expression of b-glucuronidase (bG) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. bG was tethered on the plasma membrane of three different human cancer cell lines: human colon carcinoma (LS174T), lung adenocarcinoma (CL1-5) and bladder carcinoma (EJ). Surface b-glucuronidase-expressing cells were 20 to 80-fold more sensitive to SN-38G than the parental cells. Intravenous CPT-11 produced significantly greater suppression of CL1-5 and LS174 T tumors that expressed bG as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered bG (Ad.bG) increased the sensitivity of cancer cells to SN-38G even at multiplicity of infections as low as 0.16, indicating bystander killing of non-transduced cancer cells. Importantly, intratumoral injection of Ad.bG significantly enhanced the in vivo antitumor activity of CPT-11 as compared with treatment with CPT-11 or Ad vectors alone. This study shows that Ad.bG has potential to boost the therapeutic index of CPT-11.

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An improved human carboxylesterase for enzyme/prodrug therapy with CPT-11

Cited by 44 publications

References 25 publications

Stem and progenitor cell-mediated tumor selective gene therapy

Stem and progenitor cell-mediated tumor selective gene therapy

Neural Stem Cell-Mediated Delivery of Irinotecan-Activating Carboxylesterases to Glioma: Implications for Clinical Use

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

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