Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer

Pier Paolo Claudio, Candace M. Howard, Carmen Pacilio, Caterina Cinti, Gaetano Romano, Corrado Minimo, Nadir M. Maraldi, John D. Minna, Larry Gelbert, Lorenzo Leoncini, Gian Marco Tosi, Pietro Hicheli, Mario Caputi, Giovan Giacomo Giordano, Antonio Giordano

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Abstract

The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 107 infectious units/ml was obtained. Retrovirus- mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a 'bona fide' tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.

Original languageEnglish (US)
Pages (from-to)372-382
Number of pages11
JournalCancer Research
Volume60
Issue number2
StatePublished - Jan 15 2000

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Retinoblastoma Genes
Retroviridae
Lung
Mutation
Growth
Genes
Neoplasms
Lung Neoplasms
Moloney murine leukemia virus
Retinoblastoma Protein
Retinoblastoma
Neoplasm Genes
Tumor Cell Line
Tumor Suppressor Genes
Nude Mice
Genetic Therapy
Sequence Analysis
Carcinogenesis
Injections

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Claudio, P. P., Howard, C. M., Pacilio, C., Cinti, C., Romano, G., Minimo, C., ... Giordano, A. (2000). Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Cancer Research, 60(2), 372-382.

Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. / Claudio, Pier Paolo; Howard, Candace M.; Pacilio, Carmen; Cinti, Caterina; Romano, Gaetano; Minimo, Corrado; Maraldi, Nadir M.; Minna, John D.; Gelbert, Larry; Leoncini, Lorenzo; Tosi, Gian Marco; Hicheli, Pietro; Caputi, Mario; Giordano, Giovan Giacomo; Giordano, Antonio.

In: Cancer Research, Vol. 60, No. 2, 15.01.2000, p. 372-382.

Research output: Contribution to journalArticle

Claudio, PP, Howard, CM, Pacilio, C, Cinti, C, Romano, G, Minimo, C, Maraldi, NM, Minna, JD, Gelbert, L, Leoncini, L, Tosi, GM, Hicheli, P, Caputi, M, Giordano, GG & Giordano, A 2000, 'Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer', Cancer Research, vol. 60, no. 2, pp. 372-382.
Claudio, Pier Paolo ; Howard, Candace M. ; Pacilio, Carmen ; Cinti, Caterina ; Romano, Gaetano ; Minimo, Corrado ; Maraldi, Nadir M. ; Minna, John D. ; Gelbert, Larry ; Leoncini, Lorenzo ; Tosi, Gian Marco ; Hicheli, Pietro ; Caputi, Mario ; Giordano, Giovan Giacomo ; Giordano, Antonio. / Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. In: Cancer Research. 2000 ; Vol. 60, No. 2. pp. 372-382.
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abstract = "The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5{\%}) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 107 infectious units/ml was obtained. Retrovirus- mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92{\%} reduction, P = 0.003) and lacZ-transduced tumors (93{\%} reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a 'bona fide' tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.",
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AU - Claudio, Pier Paolo

AU - Howard, Candace M.

AU - Pacilio, Carmen

AU - Cinti, Caterina

AU - Romano, Gaetano

AU - Minimo, Corrado

AU - Maraldi, Nadir M.

AU - Minna, John D.

AU - Gelbert, Larry

AU - Leoncini, Lorenzo

AU - Tosi, Gian Marco

AU - Hicheli, Pietro

AU - Caputi, Mario

AU - Giordano, Giovan Giacomo

AU - Giordano, Antonio

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N2 - The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 107 infectious units/ml was obtained. Retrovirus- mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a 'bona fide' tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.

AB - The retinoblastoma (Rb) family consists of the tumor suppressor pRb/p105 and related proteins p107 and pRb2/p130. Recent immunohistochemical studies of the retinoblastoma family of proteins in 235 specimens of lung cancer show the tightest inverse association between the histological grading in the most aggressive tumor types and pRb2/p130. This led us to study a panel of human lung cancers for mutations in the RB2/p130 gene. Mutations in the Rb-related gene RB2/p130 were detected in 11 of 14 (78.5%) primary lung tumors by single-strand conformation polymorphism and sequence analysis. A Moloney leukemia virus-based retroviral system was set up, and a comparable viral concentration of 1 x 107 infectious units/ml was obtained. Retrovirus- mediated delivery of wild-type RB2/p130 to the lung tumor cell line H23 potently inhibited tumorigenesis in vitro and in vivo, as shown by the dramatic growth arrest observed in a colony assay and the suppression of anchorage-independent growth potential and tumor formation in nude mice. The tumors transduced with the RB2/p130 retrovirus diminished in size after a single injection, and a 12-fold reduction in tumor growth after RB2/p130 transduction compared with the Pac-transduced tumors (92% reduction, P = 0.003) and lacZ-transduced tumors (93% reduction, P < 0.001) was found to be statistically significant. These findings provide the missing confirmation that RB2/p130 is a 'bona fide' tumor suppressor gene and strengthen the hypothesis that it may be a candidate for cancer gene therapy for lung cancer.

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