Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model

Toshiyoshi Fujiwara, De Wei Cai, Renee N. Georges, Tapas Mukhopadhyay, Elizabeth A. Grimm, Jack A. Roth

Research output: Contribution to journalArticle

208 Citations (Scopus)

Abstract

Background: Mutations in the p53 tumour suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumours. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 CGy) female BALB/C nu/nu mice were inoculated in-tratracheally with 2 × 106 H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an in-tratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62%-80% of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62%-100% of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer. (J Natl Cancer Inst 86: 1458-1462, 1994)

Original languageEnglish
Pages (from-to)1458-1462
Number of pages5
JournalJournal of the National Cancer Institute
Volume86
Issue number19
DOIs
Publication statusPublished - May 5 1994
Externally publishedYes

Fingerprint

Lung Cancer
Therapeutic Uses
Tumors
Lung Neoplasms
Genes
Tumor
Cell
Mouse
Cells
Neoplasms
Gene
Mutation
Proliferation
Infection
Cell Proliferation
Model
Cancer
p53 Genes
Dilution
Restoration

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging
  • Oncology
  • Cancer Research

Cite this

Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. / Fujiwara, Toshiyoshi; Cai, De Wei; Georges, Renee N.; Mukhopadhyay, Tapas; Grimm, Elizabeth A.; Roth, Jack A.

In: Journal of the National Cancer Institute, Vol. 86, No. 19, 05.05.1994, p. 1458-1462.

Research output: Contribution to journalArticle

Fujiwara, Toshiyoshi ; Cai, De Wei ; Georges, Renee N. ; Mukhopadhyay, Tapas ; Grimm, Elizabeth A. ; Roth, Jack A. / Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. In: Journal of the National Cancer Institute. 1994 ; Vol. 86, No. 19. pp. 1458-1462.
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abstract = "Background: Mutations in the p53 tumour suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumours. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 CGy) female BALB/C nu/nu mice were inoculated in-tratracheally with 2 × 106 H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an in-tratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62{\%}-80{\%} of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62{\%}-100{\%} of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer. (J Natl Cancer Inst 86: 1458-1462, 1994)",
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AU - Cai, De Wei

AU - Georges, Renee N.

AU - Mukhopadhyay, Tapas

AU - Grimm, Elizabeth A.

AU - Roth, Jack A.

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N2 - Background: Mutations in the p53 tumour suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumours. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 CGy) female BALB/C nu/nu mice were inoculated in-tratracheally with 2 × 106 H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an in-tratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62%-80% of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62%-100% of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer. (J Natl Cancer Inst 86: 1458-1462, 1994)

AB - Background: Mutations in the p53 tumour suppressor gene (also known as TP53) are common in human lung cancers. The wild-type form of p53 is dominant over the mutant; thus, restoration of wild-type p53 function in lung cancer cells may suppress their growth as tumours. Purpose: We investigated the therapeutic efficacy of direct administration of a retroviral wild-type p53 (wt-p53) expression vector (LNp53B) in an orthotopic human lung cancer model in nu/nu mice. Methods: Proliferation of H226Br cells was determined by cell counting after infection with LNp53B in vitro. Irradiated (350 CGy) female BALB/C nu/nu mice were inoculated in-tratracheally with 2 × 106 H226Br cells (whose p53 gene has a homozygous mutation at codon 254) and treated beginning 3 days later with an in-tratracheal instillation of LNp53B retroviral supernatant for 3 days. Results: Infection with LNp53B inhibited proliferation of H226Br cells in vitro. Thirty days after tumor cell inoculation, 62%-80% of the control mice showed macroscopic tumors of the right main stem bronchus. LNp53B suppressed H226Br tumor formation in 62%-100% of mice, and the effect was abrogated by dilution of the retroviral supernatant with inactive vector. Conclusions: Direct administration of a retroviral vector expressing wt-p53 may inhibit local growth in vivo of human lung cancer cells with abnormal p53 expression. Implications: Development of gene-replacement treatment strategies based on the type of mutations found in target cancers is warranted and may lead to the development of new adjunctive therapies and gene-specific prevention strategies for lung cancer. (J Natl Cancer Inst 86: 1458-1462, 1994)

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