Adenovirus-Mediated Wild-Type p53Gene Transfer into Head and Neck Cancers

Frank, Douglas K.; Bruso, Patricia A.

doi:10.1385/1-59259-086-1:537

Cited by 59 publications

(79 citation statements)

References 6 publications

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“…Expression of the gene product is transient and phase I clinical trials have shown the virus to be safe and well tolerated at the highest doses of 10 11 PFU. [67][68][69][70][71][72][73] Studies have demonstrated the feasibility of both intravascular 74 and intratumoral 75 administration.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

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Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviralmediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21 CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

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“…Phase I and phase II trials using a recombinant p53 adenovirus (Ad-p53) demonstrated little toxicity and encouraging results in the adjuvant setting. 15 In combination with chemotherapy, several trials have administered a replication-selective adenovirus (ONYX-015) designed to preferentially replicate in and lyse p53-deficient cancer cells while sparing normal cells. 16,17 These phase II studies demonstrated objective responses at the site of injection, in patients with multiple lesions.…”

Section: Discussionmentioning

confidence: 99%

Tissue distribution of liposome-mediated epidermal growth factor receptor antisense gene therapy

et al. 2003

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Despite the widespread use of liposome-mediated gene transfer in cancer therapy protocols, little is known about the tissue distribution of intralesionally administered DNA. We have previously shown that antisense gene therapy targeting the epidermal growth factor receptor (EGFR) inhibited tumor growth in a human head and neck squamous cell carcinoma (HNSCC) xenograft model. Further investigation demonstrated lack of systemic toxicity with intramuscular or intratumoral administration of this liposomal-DNA complex. In the present study, we compared two approaches to determine the presence of exogenous DNA in the plasma and tissues of mice treated with intramuscular injection of EGFR antisense gene therapy. PCR analysis using genomic DNA plus plasmid DNA as template was 83-fold more sensitive than PCR using a mixture of total RNA and plasmid DNA as template. With the more sensitive method (able to detect fewer than 500 molecules of EGFR antisense DNA in 1 mg of genomic DNA), foreign DNA was detected in all organs up to 1 month following a single injection. In contrast, using RNA plus plasmid DNA as template, exogenous DNA was only detected at the injection site at 1 week, and was undetectable at 1 month. Optical imaging studies demonstrated plasmid DNA only at the injection site. Although less sensitive than PCCR, Southern blot hybridization showed no evidence of integration of foreign DNA into the host genome in vitro or in vivo. These results emphasize the importance of defining the assays used to detect foreign DNA and suggest that the ability to detect intralesionally administered liposomal gene therapy, in organs distant from the injection site, is directly correlated with the sensitivity of the method employed.

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“…However, the functions of the mda-7 gene and its downstream pathways remain unknown. Consequently, to understand better how mda-7 functions and to help broaden the scope of current anticancer gene therapy strategies, [7][8][9] we tested the antitumor effects of a novel adenoviral vector carrying the mda-7 gene (Admda-7) on non-small cell lung cancer lines and investigated the underlying mechanisms of tumor killing.…”

Section: Introductionmentioning

confidence: 99%

Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro

et al. 2000

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The melanoma differentiation-associated gene-7 (mda-7), cloned from a human melanoma cell line H0-1, is known to induce tumor cell-selective growth inhibition in breast cancer cells in vitro and loss of tumorigenicity ex vivo. Yet, the mechanisms underlying these effects are still unknown. Therefore, we investigated these mechanisms on the molecular level in human non-small cell lung carcinoma (NSCLC) cells in vitro. Overexpression of mda-7 protein by Ad-mda-7 significantly suppressed proliferation and induced G2/M cell cycle arrest in wild-type p53 (A549, H460), and p53-null (H1299) non-small cell lung cancer cell lines, but not in normal human lung fibroblast (NHLF) cells. p53, Bax,

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Adenovirus-Mediated Wild-Type p53Gene Transfer into Head and Neck Cancers

Cited by 59 publications

References 6 publications

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

Tissue distribution of liposome-mediated epidermal growth factor receptor antisense gene therapy

Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro

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