Adenovirus-Mediated p53 Gene Transfer in Advanced Non-Small-Cell Lung Cancer

Swisher, Stephen G.; Roth, Jack A.; Nemunaitis, John; Lawrence, David; Kemp, Bonnie L.; Carrasco, C. Humberto; Connors, Deanna E; El‐Naggar, Adel K.; Fossella, Frank V.; Glisson, Bonnie S.; Hong, Waun Ki; Khuri, Fadlo R.; Kurie, Jonathan M.; Lee, John; Lee, Jin S.; Mack, Michael J.; Merritt, James A.; Nguyen, Dao M.; Nesbitt, Jonathan C.; Pérez-Soler, Román; Pisters, Katherine M.W.; Putnam, Joe B.; Richli, William R.; Savin, Michael A.; Schrump, David S.; Shin, Dong M.; Shulkin, Allan; Walsh, Garrett L.; Wait, Juliette; Weill, David; Waugh, M. Kimberly A.

doi:10.1093/jnci/91.9.763

Cited by 441 publications

(198 citation statements)

References 21 publications

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“…[1][2][3][4][5][6][7][32][33][34] Additionally, in clinical trials, the restoration of wild-type p53 gene does not always lead to tumor regression or tumor growth inhibition. [8][9][10] Hence, there exists a need for identification of alternative candidates for effective gene therapy, in particular under conditions where p53 is ineffective. When p73 was identified, it was reported that p73 is not induced by DNA damage, 11 but later on it was found that p73 is indeed induced by a wide variety of DNA-damage-inducing drugs like adriamycin, etoposide, cisplatin, etc.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7] Moreover, in clinical trials the restoration of wild type p53 gene does not always lead to tumor regression or tumor growth inhibition suggesting resistance of some tumors to exogenous p53. [8][9][10] p73 is a member of p53 gene family and encodes proteins, which have significant homology with p53 both structurally and functionally. p73 can bind to p53 responsive elements and upregulate some of the p53 target genes suggesting that it has the potential for functional overlap with p53.…”

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confidence: 99%

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p73β-expressing recombinant adenovirus: a potential anticancer agent

et al. 2005

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Tumor suppressor p53-based gene therapy strategy is ineffective in certain conditions. p73, a p53 homologue, could be a potential alternative gene therapy agent as it has been found to be an important determinant of chemosensitivity in cancer cells. Previously, we have reported the generation of a replication-deficient adenovirus expressing p73b (Ad-p73). In this study, we evaluated the therapeutic potential of Ad-p73 against a panel of cancer cells (n ¼ 12) of different tissue origin. Ad-p73 infected all the cell lines tested very efficiently resulting in several-fold increase in p73b levels, which is also functional as it activated the known target gene p21 WAF1/CIP1 . Infection with Ad-p73 resulted in potent cytotoxicity in all the cell lines tested. The mechanism of p73-induced cytotoxicity in these cell lines is found to be due to a combination of cell cycle arrest and induction of apoptosis. In addition, exogenous overexpression of p73 by Ad-p73 infection increased the chemosensitivity of cancer cells by many fold to commonly used drug adriamycin. Moreover, Ad-p73 is more efficient than Ad-p53 in enhancing the chemosensitivity of mutant p53 harboring cells. Furthermore, Ad-p73 infection did not induce apoptosis in human normal lung fibroblasts (HEL 299) and human immortalized keratinocytes (HaCaT). These results suggest that Ad-p73 is a potent cytotoxic agent specifically against cancer cells and could be developed as a cancer gene therapy agent either alone or in combination with chemotherapeutic agents.

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Section: Discussionmentioning

confidence: 99%

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p73β-expressing recombinant adenovirus: a potential anticancer agent

et al. 2005

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“…71,72 Wtp53 -mediated tumor growth inhibition is a complex process. These findings have demonstrated that wtp53 -induced tumor regression may be due, at least in part, to antiangiogenesis mediated through the downmodulation of bFGF -BP.…”

Section: Discussionmentioning

confidence: 99%

Downmodulation of bFGF-binding protein expression following restoration of p53 function

et al. 2001

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Angiogenesis is a requirement for solid tumor growth. Therefore, inhibition of this neovascularization is one mechanism by which restoration of wtp53 function may lead to tumor regression. Here we report that adenoviral vector -mediated wild -type p53 transduction results in growth inhibition of squamous cell carcinoma of the head and neck tumor cells both in vitro and in a xenograft mouse model. This growth inhibition is associated with the down -regulation of the expression of fibroblast growth factor binding protein, a secreted protein required for the activation of angiogenic factor basic FGF. These findings suggest that wtp53 -induced tumor regression is due, at least in part, to antiangiogenesis mediated by the downmodulation of fibroblast growth factor binding protein. Cancer Gene Therapy ( 2001 ) 8, 771 -782

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“…[3][4][5][6][7][8][9] In addition, several clinical trials with replication-deficient adenoviruses that express p53 have demonstrated an excellent safety profile. [10][11][12][13][14][15] Recently, such a vector has been approved for clinical application in China and several phase 3 trials are ongoing in the United States. However, overall, the efficacy of this approach has been relatively low.…”

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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Adenovirus-Mediated p53 Gene Transfer in Advanced Non-Small-Cell Lung Cancer

Abstract: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Cited by 441 publications

References 21 publications

p73β-expressing recombinant adenovirus: a potential anticancer agent

p73β-expressing recombinant adenovirus: a potential anticancer agent

Downmodulation of bFGF-binding protein expression following restoration of p53 function

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

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