Development of a Tumor-Selective Approach to Treat Metastatic Cancer

Aboody, Karen S.; Bush, Rebecca A.; Garcia, Elizabeth; Metz, Marianne Z.; Najbauer, Joseph; Justus, Kristine A.; Phelps, Doris A.; Remack, Joanna S.; Yoon, Karina J.; Gillespie, Shanna; Kim, Seung Up; Glackin, Carlotta A.; Potter, Philip M.; Danks, Mary K.

doi:10.1371/journal.pone.0000023

Cited by 115 publications

(149 citation statements)

References 39 publications

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“…13,14 These studies demonstrated that 90% of mice bearing multiple neuroblastoma metastases were disease-free, following treatment with neural progenitor cells expressing rCE and CPT-11 administration. In addition, no increase in toxicity was observed in these animals and doses of CPT-11 were used that are tolerable in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…Since the activation of CPT-11 by humans is relatively inefficient, we have proposed and developed an enzyme/prodrug therapy approach, using a rabbit liver CE (rCE), that can proficiently activate the drug. [8][9][10][11][12][13][14] Consequently, expression of rCE in human tumor cells, grown either in culture or as xenografts in immune-deprived mice, results in increased sensitivity to CPT-11. 8,12 However, the application of rCE to an enzyme/prodrug therapy approach in humans may be limited due to the potential immunogenicity of the lagomorph protein.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of (1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC 50 value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would be suitable for the in vivo application of CE/CPT-11 enzyme/prodrug therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…CM-DiI is a fluorescent dye suitable for tracking cells in vivo because it is non-diffusible and persists for at least 10 weeks by strongly binding to cellular thiols via a covalent bond. 27 Fluorescence staining analysis…”

Section: Mice Xenograft Model Derived From Mda-mb-231 Cellsmentioning

confidence: 99%

Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models

et al. 2012

Cancer Gene Ther

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As human amniotic fluid-derived stem cells (hAFSCs) are capable of multiple lineage differentiation, extensive self-renewal and tumor targeting, they may be valuable for clinical anticancer therapies. In this study, we used hAFSCs as vehicles for targeted delivery of therapeutic suicide genes to breast cancer cells. hAFSCs were engineered to produce AF2.CD-TK cells in order to express two suicide genes encoding bacterial cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSV-TK) that convert non-toxic prodrugs, 5-fluorocytosine (5-FC) and mono-phosphorylate ganciclovir (GCV-MP), into cytotoxic metabolites, 5-fluorouracil (5-FU) and triphosphate ganciclovir (GCV-TP), respectively. In cell viability test in vitro, AF2.CD-TK cells inhibited the growth of MDA-MB-231 human breast cancer cells in the presence of the 5-FC or GCV prodrugs, or a combination of these two reagents. When the mixture of 5-FC and GCV was treated together, an additive cytotoxic effect was observed in the cell viability.In animal experiments using female BALB/c nude mouse xenografts, which developed by injecting MDA-MB-231 cells, treatment with AF2.CD-TK cells in the presence of 5-FC and GCV significantly reduced tumor volume and weight to the same extent seen in the mice treated with 5-FU. Histopathological and fluorescent staining assays further showed that AF2.CD-TK cells were located exactly at the site of tumor formation. Furthermore, breast tissues treated with AF2.CD-TK cells and two prodrugs maintained their normal structures (for example, the epidermis and reticular layers) while breast tissue structures in 5-FU-treated mice were almost destroyed by the potent cytotoxicity of the drug. Taken together, these results indicate that AF2.CD-TK cells can serve as excellent vehicles in a novel therapeutic cell-based gene-directed prodrug system to selectively target breast malignancies. INTRODUCTIONBreast cancer is one of the most common malignancies and the leading cause of cancer-related death in women worldwide. 1 Chemotherapy has been the main treatment for highly metastatic breast cancer. Although various chemotherapeutic agents are currently available, their applications are limited because of undesirable side effects, substantial toxicities to normal tissues and high-dose requirements resulting from drug resistance. In this study, we present a novel, low-toxic and effective chemotherapeutic strategy for treating breast cancer using genetically engineered stem cells to deliver suicide genes.Suicide genes are viral or bacterial enzymes that can convert non-toxic prodrugs into toxic metabolites that cause tumor cell death when introduced into tumor sites. Among a number of suicide gene/prodrug combinations, cytosine deaminase (CD)/ 5-fluorocytosine (5-FC) and herpes simplex virus thymidine kinase (HSV-TK)/ganciclovir (GCV) have been most extensively studied. The product of the CD gene converts a far less toxic prodrug, 5-FC, into its cytotoxic form, 5-FU, a nucleotide analog that induces cell death by inhibiting thymidyla...

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“…[7][8][9] In addition, NSCs can target brain metastasis in leptomeningeal medulloblastoma, breast cancer, melanoma and disseminated neuroblastoma. 8,[10][11][12] Therefore, we adopted NSCs as a targeting delivery system for subdural medulloblastomas, which serves as a disseminated tumor model. Gene-directed enzyme prodrug therapy has been one of the therapeutic strategies in stem cell-based gene therapy.…”

Section: Introductionmentioning

confidence: 99%

“…15 The activation level of CPT-11 in human plasma is very low because of the lack of CE activity in human blood. 16 As a result, a rabbit liver CE (rCE) that is 100-fold more efficient than human CE 10,12,[17][18][19] can be used for enzyme and prodrug therapy in combination with CPT-11 to improve therapeutic efficacy. 17,19 In the present study, we administered rCE expressing NSCs intravenously (i.v.)…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

Lim

et al. 2011

Cancer Gene Ther

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The prognosis of medulloblastoma has improved significantly because of advances in multi-modal treatments; however, metastasis remains one of the prognostic factors for a poor outcome and is usually associated with tumor recurrence. We evaluated the migratory potential and therapeutic efficacy of genetically engineered human neural stem cells (NSCs) that encode a prodrug enzyme in the subdural medulloblastoma model. We genetically modified HB1.F3 (F3) immortalized human NSCs to express rabbit carboxylesterase (rCE) enzyme, which efficiently converts the prodrug CPT-11 (Irinotecan) into an active anti-cancer agent (SN-38). To simulate clinical metastatic medulloblastomas, we implanted human medulloblastoma cells into the subdural spaces of nude mice. rCE expressing NSCs (F3.rCE) were labeled with fluorescence magnetic nanoparticle for in vivo imaging. The therapeutic potential of F3.rCE was confirmed using a mouse subdural medulloblastoma model. The majority of intravenously (i.v.) injected, F3.rCE cells migrated to the subdural medulloblastoma site and a small number of F3.rCE cells were found in the lungs, pancreas, kidney and liver. Animals that received F3.rCE cells in combination with prodrug CPT-11 survived significantly longer (median survival: 142 days) than control mice that received F3.rCE cells only (median survival: 80 days, Po0.001) or CPT-11 only (median survival: 118 days, Po0.001). In conclusion, i.v. injected F3.rCE NSCs were able to target subdural medulloblastomas and demonstrate therapeutic efficacy. Our study provides data that supports further investigation of stem-cell-based gene therapy against metastatic medulloblastomas.

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Development of a Tumor-Selective Approach to Treat Metastatic Cancer

Cited by 115 publications

References 39 publications

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

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

Human amniotic fluid-derived stem cells expressing cytosine deaminase and thymidine kinase inhibits the growth of breast cancer cells in cellular and xenograft mouse models

Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

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