Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector.
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.
Ramesh
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R
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. rramesh@mdanderson.org
Saeki
T
T
Templeton
N S
NS
Ji
L
L
Stephens
L C
LC
Ito
I
I
Wilson
D R
DR
Wu
Z
Z
Branch
C D
CD
Minna
J D
JD
Roth
J A
JA
D017766:Acid Anhydride Hydrolases; D000818:Animals; D005229:Fatty Acids, Monounsaturated; D005260:Female; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins; D011506:Proteins / Q000187:drug effects / Q000235:genetics* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds; D013997:Time Factors; D019076:Transgenes; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D009363:Neoplasm Proteins; D011506:Proteins; D000644:Quaternary Ammonium Compounds; D000099170:Bis(5'-adenosyl)triphosphatase; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane