An Orthotopic Bladder Cancer Model for Gene Delivery Studies

Kasman, Laura; Voelkel‐Johnson, Christina

doi:10.3791/50181

Cited by 10 publications

(16 citation statements)

References 25 publications

(12 reference statements)

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“…Then luciferase-expressing EWS cells were injected with a glass Hamilton syringe and 45° bevel 26-gauge needle. For the orthotopic BUC mouse model, the NU/J mice were anesthetized with 2.5% isoflurane and cells were implanted following the procedures, as described previously (60). A 24-gauge Teflon-coated catheter was introduced into the lumen of the bladder through the urethra.…”

Section: Methodsmentioning

confidence: 99%

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Liu¹,

Xu²,

Jeught³

et al. 2018

Journal of Clinical Investigation

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A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.

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Section: Methodsmentioning

confidence: 99%

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Liu¹,

Xu²,

Jeught³

et al. 2018

Journal of Clinical Investigation

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“…For clinical relevance, we wished to use an orthotopic model of bladder cancer and, since TCCSUP cells fail to establish tumors when instilled intravesically (0/3 mice, LK unpublished results), we chose the murine bladder cancer cell line MB49, which efficiently forms tumors in the bladder [25]. To assess adenoviral infectivity in this cell line, we exposed MB49 cells to increasing concentrations of AdGFP and quantified GFP positive cells using flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

“…For in vivo studies, mice were orthotopically implanted with MB49 cells [25]. Eight days after implantation of tumor cells, an adenovirus expressing the luciferase transgene under control of a CMV promoter (Ad.Luc) was delivered either alone or in combination with 400 μg of NPGDE-1,4 Bis.…”

Section: Resultsmentioning

confidence: 99%

“…MB49 bladder cancer cells are derived from C57BL6 mice and efficiently grow in vivo following intravesical instillation [25]. These cells are relatively resistant to adenoviral infection (Figure 1), and therefore made an excellent model to evaluate the impact of polymers on adenoviral transduction.…”

Section: Discussionmentioning

confidence: 99%

“…Implantation of MB49 cells and instillation of adenovirus were performed as previously described [25]. Briefly, eight days after implantation of MB49 cells, an adenovirus expressing the luciferase transgene under control of a CMV promoter (Ad.Luc) was instilled at the indicated concentrations in the absence or presence of polymer.…”

Section: Methodsmentioning

confidence: 99%

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Polymer-enhanced delivery increases adenoviral gene expression in an orthotopic model of bladder cancer

Gosnell

Kasman

Potta

et al. 2014

Journal of Controlled Release

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Gene therapy has garnered significant attention as a therapeutic approach for bladder cancer but efficient delivery and gene expression remain major hurdles. The goal of this study was to determine if cationic polymers can enhance adenoviral gene expression in cells that are difficult to transduce in vitro and to subsequently investigate lead candidates for their capacity to increase adenoviral gene expression in an orthotopic in vivo model of bladder cancer. In vitro screening of linear polyamine-based and aminoglycoside-based polymer libraries identified several candidates that enhanced adenoviral reporter gene expression in vitro. The polyamine-based polymer NPGDE-1,4 Bis significantly enhanced adenoviral gene expression in the orthotopic model of bladder cancer but unfortunately further use of this polymer was limited by toxicity. In contrast, the aminoglycoside-based polymer paromomycin-BGDE, enhanced adenoviral gene expression within the bladder without adverse events. Our study demonstrates for the first time that cationic polymers can enhance adenoviral gene expression in an orthotopic model of bladder cancer, thereby providing the foundation for future studies to determine therapeutic benefits of polymer-adenovirus combination in bladder cancer gene therapy.

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In vivo biodistribution and toxicity of intravesical administration of quantum dots for optical molecular imaging of bladder cancer

Pan

Chang

Marcq

et al. 2017

Sci Rep

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Optical molecular imaging holds the potential to improve cancer diagnosis. Fluorescent nanoparticles such as quantum dots (QD) offer superior optical characteristics compared to organic dyes, but their in vivo application is limited by potential toxicity from systemic administration. Topical administration provides an attractive route for targeted nanoparticles with the possibility of minimizing exposure and reduced dose. Previously, we demonstrated successful ex vivo endoscopic imaging of human bladder cancer by topical (i.e. intravesical) administration of QD-conjugated anti-CD47. Herein we investigate in vivo biodistribution and toxicity of intravesically instilled free QD and anti-CD47-QD in mice. In vivo biodistribution of anti-CD47-QD was assessed with inductively coupled plasma mass spectrometry. Local and systemic toxicity was assessed using blood tests, organ weights, and histology. On average, there was no significant accumulation of QD outside of the bladder, although in some mice we detected extravesical biodistribution of QD suggesting a route for systemic exposure under some conditions. There were no indications of acute toxicity up to 7 days after instillation. Intravesical administration of targeted nanoparticles can reduce systemic exposure, but for clinical use, nanoparticles with established biosafety profiles should be used to decrease long-term toxicity in cases where systemic exposure occurs.

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An Orthotopic Bladder Cancer Model for Gene Delivery Studies

Cited by 10 publications

References 25 publications

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

Polymer-enhanced delivery increases adenoviral gene expression in an orthotopic model of bladder cancer

In vivo biodistribution and toxicity of intravesical administration of quantum dots for optical molecular imaging of bladder cancer

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