Adenovirus-Mediated Wild-Type  p53 Gene Transfer in Patients Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Results of a Multicenter Phase II Study

Schüler, Martin; Herrmann, Richard; Grève, Jacques De; Stewart, A. Keith; Gatzemeier, U.; Stewart, David J.; Laufman, Leslie R.; Gralla, Richard J.; Kuball, Jürgen; Buhl, Roland; Heußel, Claus Peter; Kommoss, Friedrich; Perruchoud, André P.; Shepherd, Frances A.; Fritz, Mary Ann; Horowitz, Jo Ann; Huber, Christoph; Rochlitz, Christoph

doi:10.1200/jco.2001.19.6.1750

Cited by 190 publications

(100 citation statements)

References 32 publications

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“…RNA concentration and integrity were determined by measuring the absorbance at 260 nm and by electrophoresis on a 1% agarose gel. For reverse transcription (RT)-PCR, 5 mg of total RNA was reverse transcribed using SUPERSCRIPT RT (Invitrogen) and an oligo (dT) [12][13][14][15][16][17][18] primer (Invitrogen). Real-time RT-PCR was performed in an iCycler detection system (Bio-Rad, Hercules, CA).…”

Section: Evaluation Of Tumor Burdenmentioning

confidence: 99%

“…RNA concentration and integrity were determined by measuring the absorbance at 260 nm and by electrophoresis on 1% agarose gel. For RT-PCR, 5 mg of total RNA was reverse transcribed using SUPERSCRIPT RT (Invitrogen) and oligo (dT) [12][13][14][15][16][17][18] 48 The primer sequences designed for amplification of a b-actin cDNA fragment (541 bp) were 5 0 -GTGGGGCGCCCCAGGCACCA-3 0 and 5 0 -GTCCT TAATGTCACGCACGATTTC-3 0 . Amplification was performed according to Laux et al 49 PCR products were analyzed by electrophoresis on a 0.8% agarose gel and visualized by ethidium bromide (Anco and Rhenium Industries Ltd, Jerusalem, Israel).…”

Section: Rt-pcrmentioning

confidence: 99%

“…Gene therapy regimens are typically delivered to the lung through intratumoral, intrabronchial or intrapleural injections. 3,11,12 These types of direct intratracheal administration of therapeutic agents are technically cumbersome, uncomfortable and invasive. By contrast, aerosol delivery is more efficient and a simpler mode of gene therapy transport to the lungs.…”

Section: Introductionmentioning

confidence: 99%

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WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

et al. 2009

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The Wilms' tumor gene 1 (WT1) is a universal tumor antigen and consequently a good therapeutic target for the development of gene therapy strategies. Earlier, we reported the in vitro efficacy of WT1 RNAi in the inhibition of B16F10 murine melanoma cell line growth. In this study, we used an aerosol system to deliver WT1 RNAi complexes, polyethyleneimine (PEI)-WT1-1 or PEI-WT1-2, to the lungs of mice with B16F10 lung metastasis. This treatment produced a statistically significant (P ¼ 0.020) reduction in the number and size of lung tumor foci, resulting in decreased lung weight and tumor index in treated mice compared with controls. The WT1 RNAi treatment also reduced the number and size of tumor blood vessels, suggesting decreased angiogenesis. Furthermore, the treated lung tissue showed cells in the tumor infiltrations undergoing apoptosis and elevated expression of the proapoptotic genes Bcl-xS and Bax, suggesting an activation of the intrinsic apoptotic pathway. Overall, WT1-1 treatment prolonged the mean survival time of tumor-bearing mice in comparison with the control and WT1-2-treated mice. Our data show that WT1 gene silencing in vivo by aerosol delivery of PEI-WT1 RNAi complexes is an effective therapeutic strategy for the treatment of lung metastases.

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Section: Evaluation Of Tumor Burdenmentioning

confidence: 99%

Section: Rt-pcrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

et al. 2009

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“…16 Clinical trials in patients with lung cancer have also shown only very limited clinical responses. 10,11,17 Replicating adenoviral vectors have the ability to multiply within the target cell and infect surrounding cells and may overcome the limited transduction efficiency that is inherent to replication-incompetent vectors. However, despite these favorable features and their intrinsic oncolytic properties, replicating adenoviruses have also shown low efficacy for cancer therapy in animal models and early clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

et al. 2006

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Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kD and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy.

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“…19 However, in a phase II study in subjects with at least two measurable lesions, there was no difference in response rates for lesions treated with Ad.p53/chemotherapy compared with chemotherapy alone, implying Ad.p53 provided little local benefit over chemotherapy. 20 Keedy and colleagues used repeated delivery of Ad.p53 by bronchoalveolar lavage (BAL) for patients with bronchioloalveolar carcinoma (BAC). 21 BAL delivery resulted in transient expression of p53 in 19% (3 of 16), two of whom achieved stable disease.…”

Section: Replacement Of Tumor Suppressor Genesmentioning

confidence: 99%

Gene therapy for lung neoplasms

Albelda

Wiewrodt

Sterman

2002

Clinics in Chest Medicine

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SYNOPSISBoth advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

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Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Results of a Multicenter Phase II Study

Abstract: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Cited by 190 publications

References 32 publications

WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

WT1 gene silencing by aerosol delivery of PEI–RNAi complexes inhibits B16-F10 lung metastases growth

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53

Gene therapy for lung neoplasms

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