Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector

Rajagopal Ramesh, Tomoyuki Saeki, Nancy Smyth Templeton, Lin Ji, L. Clifton Stephens, Isao Ito, Deborah R. Wilson, Zheng Wu, Cynthia D. Branch, John D. Minna, Jack A. Roth

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP: Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.

Original languageEnglish (US)
Pages (from-to)337-350
Number of pages14
JournalMolecular Therapy
Volume3
Issue number3
DOIs
StatePublished - 2001

Fingerprint

Tumor Suppressor Genes
Liposomes
Lung Neoplasms
Neoplasms
Therapeutics
Survival
Neoplasm Genes
Transgenes
Genetic Therapy
Genes
Cholesterol
Neoplasm Metastasis
Gene Expression
Lung
DNA
Growth
1,2-dioleoyloxy-3-(trimethylammonium)propane

Keywords

  • FHIT
  • Gene therapy
  • Intratumoral
  • Intravenous
  • Liposome
  • Lung cancer
  • p53
  • Tumor suppressor

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector. / Ramesh, Rajagopal; Saeki, Tomoyuki; Smyth Templeton, Nancy; Ji, Lin; Stephens, L. Clifton; Ito, Isao; Wilson, Deborah R.; Wu, Zheng; Branch, Cynthia D.; Minna, John D.; Roth, Jack A.

In: Molecular Therapy, Vol. 3, No. 3, 2001, p. 337-350.

Research output: Contribution to journalArticle

Ramesh, R, Saeki, T, Smyth Templeton, N, Ji, L, Stephens, LC, Ito, I, Wilson, DR, Wu, Z, Branch, CD, Minna, JD & Roth, JA 2001, 'Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector', Molecular Therapy, vol. 3, no. 3, pp. 337-350. https://doi.org/10.1006/mthe.2001.0266
Ramesh, Rajagopal ; Saeki, Tomoyuki ; Smyth Templeton, Nancy ; Ji, Lin ; Stephens, L. Clifton ; Ito, Isao ; Wilson, Deborah R. ; Wu, Zheng ; Branch, Cynthia D. ; Minna, John D. ; Roth, Jack A. / Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector. In: Molecular Therapy. 2001 ; Vol. 3, No. 3. pp. 337-350.
@article{432b63b1252e409499e96c87fe88d430,
title = "Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector",
abstract = "Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25{\%} of tumor cells per tumor in primary tumors and 10{\%} in disseminated tumors. When treated with DOTAP: Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.",
keywords = "FHIT, Gene therapy, Intratumoral, Intravenous, Liposome, Lung cancer, p53, Tumor suppressor",
author = "Rajagopal Ramesh and Tomoyuki Saeki and {Smyth Templeton}, Nancy and Lin Ji and Stephens, {L. Clifton} and Isao Ito and Wilson, {Deborah R.} and Zheng Wu and Branch, {Cynthia D.} and Minna, {John D.} and Roth, {Jack A.}",
year = "2001",
doi = "10.1006/mthe.2001.0266",
language = "English (US)",
volume = "3",
pages = "337--350",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector

AU - Ramesh, Rajagopal

AU - Saeki, Tomoyuki

AU - Smyth Templeton, Nancy

AU - Ji, Lin

AU - Stephens, L. Clifton

AU - Ito, Isao

AU - Wilson, Deborah R.

AU - Wu, Zheng

AU - Branch, Cynthia D.

AU - Minna, John D.

AU - Roth, Jack A.

PY - 2001

Y1 - 2001

N2 - Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP: Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.

AB - Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP: Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.

KW - FHIT

KW - Gene therapy

KW - Intratumoral

KW - Intravenous

KW - Liposome

KW - Lung cancer

KW - p53

KW - Tumor suppressor

UR - http://www.scopus.com/inward/record.url?scp=0034981225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034981225&partnerID=8YFLogxK

U2 - 10.1006/mthe.2001.0266

DO - 10.1006/mthe.2001.0266

M3 - Article

VL - 3

SP - 337

EP - 350

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 3

ER -