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[Cancer Research 60, 372-382, January 15, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Mutations in the Retinoblastoma-related Gene RB2/p130 in Lung Tumors and Suppression of Tumor Growth in Vivo by Retrovirus-mediated Gene Transfer1

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 and Antonio Giordano2

Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [P. P. C., C. M. H., C. P., G. R, C. M., A. G.]; Sbarro Institute for Cancer Research and Molecular Medicine, Philadelphia, Pennsylvania 19107 [P. P. C., C. M. H., C. P., A. G.]; Dipartimento di Scienze Odontostomatologiche e Maxillo-Facciali, University of Naples "Federico II," 80100 Napoli, Italy [P. P. C.]; Istituto di Citomorfologia Normale e Patologica, Consiglio Nazionale delle Ricerche, c/o Istituti Ortopedici Rizzoli, 40136 Bologna, Italy [C. C., N. M. M.]; Laboratorio di Biologia Cellulare e Microscopia elettronica, Istituti di Ricerca "Codivilla Putti," IOR, 40100 Bologna, Italy [N. M. M.]; Hamon Center for Ther. Onc. Res., University of Texas Southwestern Medical Center, Dallas, Texas 75235-8593 [J. D. M.]; Bristol-Meyers Squibb, Princeton, New Jersey 08543-4000 [L. G.]; Institute di Anatomia e Istologia Patologica, Universita di Siena, 53100 Siena, Italy [L. L.]; Dipartimento di Scienze Oftalmologiche e Neurochirurgiche, Universita’ di Siena, 53100 Siena, Italy [G. M. T.]; Azienda Ospedaliera Cotugno, Servizio di Anatomia, Istologia e Citologia Patologica, Napoli, Italy [P. M.]; Istituto di Malattie dell’Apparato Respiratorio, II Universita’ degli Studi di Napoli, Istituto di Ricerca Cardio-Pneumologico A. O. "Monaldi," Napoli, Italy [M. C.]; and Istituto di Anatomia Patologica, Facolta’ di Medicina, II Universita’ di Napoli, Napoli 80122, Italy [G. G. G.]

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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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2000 by the American Association for Cancer Research.