p53: A Frequent Target for Genetic Abnormalities in Lung Cancer

Takahashi, Takashi; Nau, Marion M.; Chiba, Itsuo; Birrer, Michael J.; Rosenberg, Richard K.; Vinocour, Michelle; Levitt, Mark L.; Pass, Harvey I.; Gazdar, Adi F.; Minna, John D.

doi:10.1126/science.2554494

Cited by 1,083 publications

(534 citation statements)

References 29 publications

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“…[2][3][4] This tumor suppressor plays a central role in both regulation of cell proliferation and apoptosis; its normal function is lost in the majority of tumors including non small-cell lung cancer (NSCLC). 5 Thus, the hope was that reintroduction of this gene into p53-deficient tumors or overexpression in p53-positive tumors would inhibit tumor growth. (see Ref.…”

Section: Introductionmentioning

confidence: 99%

Cell cycle arrest is sufficient for p53-mediated tumor regression

et al. 2001

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Section: Introductionmentioning

confidence: 99%

Cell cycle arrest is sufficient for p53-mediated tumor regression

et al. 2001

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“…1 Among these genetic alterations, the p53 gene is the most frequent target for non-small cell lung cancer (NSCLC) development, 2 and p53 mutations appear to be associated with a poor prognosis in NSCLC patients. 3 There is compelling evidence that wild-type p53 (wt-p53) plays important roles in modulating or mediating cell cycle control, apoptosis, or genomic stability.…”

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confidence: 99%

Synergistic effects of adenovirus expressing wild-type p53 on chemosensitivity of non-small cell lung cancer cells

et al. 2000

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The infection of recombinant adenovirus expressing wild-type p53 (Ad-p53) to lung cancer cells that harbor mutant p53 genes improves their response to cis-diamminedichloroplatinum(II). In this study, we tested whether this improvement in response is also seen in wild-type p53 (wt-p53)-containing cancer cells and whether this phenomenon is universal with other commonly used chemotherapeutic agents, including etoposide, 7-ethyl-10-hydrocycamptothecin, paclitaxel, and docetaxel. Using a panel of 7 non-small cell lung cancer cell lines with wild-type (2) or abnormal (2 null, 3 point-mutated) p53, we examined in vitro cytotoxicity using a tetrazolium-based colorimetric assay (3-(4,5-diethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay) and analyzed the combined effects of Ad-p53 and chemotherapeutic agents using the isobologram method. Ad-p53 and DNA-damaging agents (cis-diamminedichloroplatinum(II), etoposide, and 7-ethyl-10-hydrocycamptothecin) showed synergistic effects in six of seven cell lines but additive effects against a p53-mutated cell line. In contrast, Ad-p53 showed additive effects with the antitubulin agents (paclitaxel and docetaxel) in all four of the cell lines tested. Furthermore, we examined this synergistic interaction between Ad-p53 and DNA-damaging agents by flow cytometric analysis and DNA fragmentation analysis. Both analyses revealed that a sublethal dose of Ad-p53 augmented the apoptotic response induced by DNA-damaging agents in six of seven cell lines. Our results suggest that Ad-p53 may synergistically enhance the chemosensitivity of the majority of non-small cell lung cancers to DNA-damaging agents due to augmentation of apoptosis. Cancer Gene Therapy (2000) 7, 537-544

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“…One of these studies specifically examined patients with NF1 and also implicated the inactivation of p53 in the development of small‐cell lung cancer in NF1 21. Multiple mutations have been associated with the development of non‐small‐cell lung cancer – mutations in p53 have been found in about 50% of non‐small‐cell lung cancers 23, 24, 25. Given these findings, one can theorize that patients with NF1 are at higher risk of developing lung cancers secondary to deletions in 17p, specifically the p53 gene.…”

Section: Discussionmentioning

confidence: 99%