Adenovirus-mediated transfer of p53 and p16INK4a results in pancreatic cancer regression in vitro and in vivo View Full Text


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Article Info

DATE

2001-02-01

AUTHORS

P Ghaneh, W Greenhalf, M Humphreys, D Wilson, L Zumstein, NR Lemoine, JP Neoptolemos

ABSTRACT

Pancreatic cancer has a very poor prognosis. Current chemotherapy and radiotherapy regimens are only moderately successful. The tumour suppressor genes p53 and p16INK4aencode cell cycle regulatory proteins that are important candidates for gene replacement therapy. Over 80% of pancreatic adenocarcinoma cases lack detectable p16 protein while over 60% contain mutated p53 protein. We used replication-deficient recombinant adenoviruses to reintroduce wild-type p16 and p53 into pancreatic cancer cells in vitro and into subcutaneous pancreatic tumours in an animal model to determine the effect on tumour growth. Significant growth inhibition was observed in all five human pancreatic cell lines with these viruses (P < 0.002) compared with similar control viruses expressing either luciferase or β-galactosidase. G1 arrest was observed in all cell lines 72 h after infection with Adp16. Infection with Adp53 caused significant levels of apoptosis (P < 0.004). Apoptosis was also observed to a lesser degree (P < 0.03) with the Adp16 vector. Subcutaneous pancreatic tumours, generated in nu-nu mice demonstrated significant growth suppression following injection of Adp53, Adp16 and a combination of both Adp53 and Adp16 (P < 0.0001). These results show that transfer of wild-type p53 and p16 produces significant growth suppression of pancreatic cancer in vitro and in vivo. More... »

PAGES

199-208

References to SciGraph publications

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  • 1999-03-04. Comparison of the effectiveness of adenovirus vectors expressing cyclin kinase inhibitors p16INK4A, p18INK4C, p19INK4D, p21WAF1/CIP1 and p27KIP1 in inducing cell cycle arrest, apoptosis and inhibition of tumorigenicity in ONCOGENE
  • 1999-12-13. Regulation of p53 in response to DNA damage in ONCOGENE
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  • 1997-04. Progress report: A randomized multicenter European stydy comparing adjuvant radiotherapy, 6 Mo chemotherapy, and combination therapy vs No-adjuvant treatment in resectable pancreatic cancer (ESPAC-1) in JOURNAL OF GASTROINTESTINAL CANCER
  • 1999-07-08. p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis in ONCOGENE
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  • 1996-09. Retrovirus–mediated wild–type P53 gene transfer to tumors of patients with lung cancer. in NATURE MEDICINE
  • 2000-03-02. p16/MTS1/INK4A suppresses prostate cancer by both pRb dependent and independent pathways in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/sj.gt.3301394

    DOI

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    DIMENSIONS

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    42 schema:description Pancreatic cancer has a very poor prognosis. Current chemotherapy and radiotherapy regimens are only moderately successful. The tumour suppressor genes p53 and p16INK4aencode cell cycle regulatory proteins that are important candidates for gene replacement therapy. Over 80% of pancreatic adenocarcinoma cases lack detectable p16 protein while over 60% contain mutated p53 protein. We used replication-deficient recombinant adenoviruses to reintroduce wild-type p16 and p53 into pancreatic cancer cells in vitro and into subcutaneous pancreatic tumours in an animal model to determine the effect on tumour growth. Significant growth inhibition was observed in all five human pancreatic cell lines with these viruses (P < 0.002) compared with similar control viruses expressing either luciferase or β-galactosidase. G1 arrest was observed in all cell lines 72 h after infection with Adp16. Infection with Adp53 caused significant levels of apoptosis (P < 0.004). Apoptosis was also observed to a lesser degree (P < 0.03) with the Adp16 vector. Subcutaneous pancreatic tumours, generated in nu-nu mice demonstrated significant growth suppression following injection of Adp53, Adp16 and a combination of both Adp53 and Adp16 (P < 0.0001). These results show that transfer of wild-type p53 and p16 produces significant growth suppression of pancreatic cancer in vitro and in vivo.
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