Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma

Abstract

Three drugs were compared for their efficacy in treating murine transitional cell carcinoma (TCC) of the bladder. Intravesical gene therapy treatments utilizing expression-targeted plasmids, where the murine cyclooxygenase-2 (Cox-2) promoter was used to drive the expression of exogenously inducible forms of caspases 3 and 9, were compared with treatment modalities employing Bacille Calmette-Guérin (BCG) and celecoxib. When administered via lavage, only the gene therapy regimen was found to be effective at restricting tumor progression following a 7-day incubation of tumor tissues. Celecoxib was also administered via the diet to allow for systemic delivery of the drug. The most efficacious celecoxib use tested yielded tumors with masses of (18.3 ± 8.4 mg) versus the gene delivery method, which yielded tumors with masses of (3.6±7.7 mg). The difference was significant (t-test, nX4, Po0.025). The results showed that the Cox-2 expression-targeted gene therapy system could efficiently bypass the bladder permeability barrier and more effectively inhibit tumor growth and development than either BCG or celecoxib treatments. Long-term data further demonstrated that the gene therapy system could effectively inhibit tumor growth and elongate life expectancy.

Clinical Applications of Recent Molecular Advances in Urologic Malignancies

“…128,146,245,247,[253][254][255][256][257][258][259][260][261][262][263][264][265][266] Among RTK, HER2 has been targeted in a multicenter phase II trial reported in 2007 by Hussain et al 267 Forty-four advanced BC patients with metastatic disease and evidence of tumor HER2 positivity by either immunohistochemical, FISH, or elevated serum extracellular HER2 domain levels, were treated with a combination of carboplatin, paclitaxel, and gemcitabine with the humanized monoclonal anti-HER2 antibody trastuzumab. 128,146,245,247,[253][254][255][256][257][258][259][260][261][262][263][264][265][266] Among RTK, HER2 has been targeted in a multicenter phase II trial reported in 2007 by Hussain et al 267 Forty-four advanced BC patients with metastatic disease and evidence of tumor HER2 positivity by either immunohistochemical, FISH, or elevated serum extracellular HER2 domain levels, were treated with a combination of carboplatin, paclitaxel, and gemcitabine with the humanized monoclonal anti-HER2 antibody trastuzumab.…”

Non‐invasive detection of bladder cancer via expression‐targeted gene delivery

“…The experiments shown in Figure were performed in an attempt to establish the relationship between detected luciferase signals and the bladder weights of mice that were treated by pUC19, P cmv‐luc , P cox2‐luc or P opn‐G.luc . The bladder weights corresponding to maximal luciferase intensity time points were extrapolated via the equation (for MB49 cells in the same C57 orthotopic model): Tumor weight (mg) = 20.088 e 0.1294t , where t is days post instillation.…”

“…B, Luciferase activities in the urine of mice treated with P opn-G.luc. Although the mean levels of G.LUC were higher versus negative controls, the differences in the means were not determined to be significant (t-test, n = 4, except for 72 h, where n = 3, p < 0.05) MB49 cells in the same C57 orthotopic model) 39 The P opn-G.luc-treated group did not produce a reliable correlation, perhaps because of weak G.LUC expression (not shown). Looking more closely at the P cox2-G.luc-treated group, the intercept of the upper confidence interval curve was 392 CPS, which indicated a tumor weighing 19.1 mg (i.e.…”

Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer

“…50 Studies of intravesical administration of virus validated this view in preclinical trails and in animal experiments. 31,51,52 Some phase I clinical trails have shown the safety and feasibility of intravesical instillation of adenovirus vectors. 53,54 Published studies have examined the biodistribution following tail vein injection of adenovirus into immunocompetent mice or intraprostatic administration in mice.…”