Evidence That Transfer of Functional p53 Protein Results in Increased Apoptosis in Prostate Cancer

Pisters, Louis L.; Pettaway, Curtis A.; Troncoso, Patricia; McDonnell, Timothy J.; Stephens, L. Clifton; Wood, Christopher G.; Anh, Kim; Brisbay, Shawn; Wang, Xuemei; Hossan, Elizabeth; Evans, Robert B.; Soto, Cindy; Jacobson, Marc G.; Parker, Kathryn; Merritt, James A.; Steiner, Mitchell S.; Logothetis, Christopher J.

doi:10.1158/1078-0432.ccr-03-0388

Cited by 45 publications

(29 citation statements)

References 25 publications

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“…We also observed a large amount of local inflammatory cell infiltration in H&E sections of the posttreatment tissues. Compared with other clinical reports (14,28), the toxic and side effects induced by rAd-p53 injection in this study was slighter, which might be owed to the relatively low dose as a result of the special lamellar lesion of OLK. However, we have to admit that as a result of the limited case number and follow-up time in this study, the evaluation of therapeutic effects of intraepithelial rAd-p53 injection in the treatment of OLK requires further expansion of the sample size and extension of the follow-up period for confirmation.…”

Section: Discussioncontrasting

confidence: 79%

“…When p53 gene deletion or mutation occurs, cells could not enter into stage G 1 and DNA reparation via p53-mediated pathway after DNA injury; therefore, cells with injured genetic information could enter into proliferation and finally induce malignant tumor (26,27). rAd-p53 shared a high sensitivity toward tumor cells, and by intratumor injection, wild-type p53 could be successfully transduced and perform multiple antitumor actions (14,27,28). Introduction of rAd-p53 into eight different types of carcinoma of head and neck could induce significant cell growth inhibition in 14.5% to 47% cells (29).…”

Section: Discussionmentioning

confidence: 99%

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In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia

Zhang

et al. 2009

Clinical Cancer Research

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Purpose: Oral leukoplakia is a well-recognized precancerous lesion of squamous cell carcinoma. When accompanied with abnormal p53 expression, it suffered a higher risk of canceration. The present study was carried out to test whether the recombinant human adenovirus-p53 could introduce wild-type p53 gene to oral leukoplakia cells and induce cell cycle arrest and apoptosis. Experimental Design: We select p53(-) oral dysplastic keratinocyte POE-9n, to observe the growth inhibition, cell cycle change, apoptosis-induced effects, and elaborate the corresponding molecular mechanism of recombinant adenovirus-p53 on POE-9n cells. Meanwhile, we evaluate the feasibility, safety, and biological activity of multipoints intraepithelial injections of recombinant adenovirus-p53 in 22 patients with dysplastic oral leukoplakia. Results: Exogenous p53 could be successfully transduced into POE-9n cells by recombinant adenovirus-p53. The optimal infecting titer in this study was multiplicity of infection (MOI) = 100. Recombinant adenovirus-p53 could strongly inhibit cell proliferation, induce apoptosis, and arrest cell cycle in stage G 1 in POE-9n cells by inducing p21 CIP/WAF and downregulating bcl-2 expression. In the posttreatment patients, p53 protein and p21 CIP/WAF protein expression were significantly enhanced, yet bcl-2 protein presented low expression. Sixteen patients showed clinical response to the treatment, and 14 patients showed obvious histopathologic improvement. Conclusion: Intraepithelial injections of recombinant human adenovirus-p53 were safe, feasible, and biologically active for patients with dysplastic oral leukoplakia. (Clin Cancer Res 2009;15(21):6724-31)

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Section: Discussioncontrasting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia

Zhang

et al. 2009

Clinical Cancer Research

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“…An additional method to deliver functional p53 using adenovirus has been developed by Introgen Therapeutics (Houston, Texas). The company's proprietary adenovirus, INGN 201, has been tested recently on patients with prostate or lung cancer, showing an increase of p53 expression and transactivation of Bak [140,141]. At present INGN 201 in combination with chemotherapeutical drugs is under investigation in phase II/III clinical trials.…”

Section: E) Restoring P53 Functionmentioning

confidence: 99%

Role of Alterations in the Apoptotic Machinery in Sensitivity of Cancer Cells to Treatment

Rodriguez-Nieto¹,

Zhivotovsky

2006

CPD

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Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for normal embryonic development and for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary or secondary role in various diseases, with essentially too little or too much apoptosis leading to proliferative or degenerative diseases, respectively. The machinery responsible for killing and degradation of the cell via apoptosis is expressed constitutively and become activated through various stimuli. Apoptotic mechanisms are operating during spontaneous regression of tumors as well as in response to treatment with anti-neoplastic drugs. The therapeutic goal in cancer treatment is to trigger tumor-selective cell death. However, resistance to treatment is a concern for many types of cancer. Since many anti-neoplastic agents induce an apoptotic type of death in susceptible cells, it is likely that defects or dysregulation of different steps of the apoptotic pathways might be an important determinant of resistance to anticancer drugs. These defects might appear at the initiation and/or execution stages of apoptosis and result in the insufficient elimination of tumor cells, which might lead either to acquired resistance to treatment, or to uncontrolled migration of cancer cells and metastasis. Hence, identification and targeting of the disabled pathway, which is most efficiently inactivated in a particular type of tumor might be the most successful approach in the future. Here we review current knowledge concerning function of apoptotic machinery in cancer cells, and how this information can be used to increase the efficiency of tumor treatment.

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“…This study has potential implications for numerous therapeutic strategies based on toxic 'suicide' gene transfer to eliminate prostate cancer cells. These strategies include the transfer of genes coding for pro-apoptotic proteins, such as p53, Bad, Bax, Fas ligand, [23][24][25][26] transferred as a single gene or in combination, 26,27 antiangiogenic factors, 28 or the diphteria toxin gene, 29 with or without additional treatments. In all these strategies, preventing toxic gene expression in healthy tissue neighboring the prostate as a function of whether the vector is injected systemically or locally is a major concern.…”

Section: Introductionmentioning

confidence: 99%

Use of the PSA enhancer core element to modulate the expression of prostate- and non-prostate-specific basal promoters in a lentiviral vector context

Chapel‐Fernandes¹,

Jordier²,

Lauro³

et al. 2006

Cancer Gene Ther

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Composite promoters combining the prostate-specific antigen (PSA) enhancer core element with promoter elements derived from gene coding for human prostate-specific transglutaminase gene, prostate-specific membrane antigen gene, prostate-specific antigen, rat probasin or phosphoglycerate kinase were characterized for their ability to specifically express the enhanced green fluorescent protein (EGFP) gene in prostate versus non-prostate cancer cell lines when transferred with a human immunodeficiency virus-1-based lentiviral vector. By themselves minimal proximal promoter elements were found to inefficiently promote relevant tissue-specific expression; in all the vectors tested, addition of the PSA enhancer core element markedly improved EGFP expression in LnCaP, a cancer prostate cell line used as a model for prostate cancer. The composite promoter was inactive in HuH7, a hepatocarcinoma cell line used as a model of neighboring non-prostate cancer cells. Among the promoters tested, the combination of the PSA enhancer and the rat probasin promoter showed both high specificity and a strong EGFP expression. Neither a high viral input nor the presence of the cPPT/CTS sequence affected composite promoter behavior. Our data suggest that composite prostatespecific promoters constructed by combining key elements from various promoters can improve and/or confer tissue specific expression in a lentiviral vector context.

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Evidence That Transfer of Functional p53 Protein Results in Increased Apoptosis in Prostate Cancer

Cited by 45 publications

References 25 publications

In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia

In vitro and Clinical Studies of Gene Therapy with Recombinant Human Adenovirus-p53 Injection for Oral Leukoplakia

Role of Alterations in the Apoptotic Machinery in Sensitivity of Cancer Cells to Treatment

Use of the PSA enhancer core element to modulate the expression of prostate- and non-prostate-specific basal promoters in a lentiviral vector context

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