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.

Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer

“…Exon specific deletions and absence of transcripts in tumors qualify FHIT as a tumor suppressor gene (Ohta et al, 1996;Sozzi et al, 1997;Greenspan et al, 1997). Further, tumor suppression resulting from the transfer of the gene into tumor cell lines also suggests that FHIT is a tumor suppressor gene (Siprashvili et al, 1997;Ramesh et al, 2001;Ishii et al, 2001). However, observation of FHIT gene deletions in normal tissues, absence of point mutations and presence of normal FHIT transcripts in tumors suggests that FHIT may not be a tumor suppressor gene (Panagopoulos et al, 1997;Mao, 1998).…”

Poly(cationic lipid)-mediated in vivo gene delivery to mouse liver

“…2 This formulation of the cationic liposomes was improved and recently employed to deliver a tumor suppressor gene for the treatment of human lung cancer. 3 A recent study showed that direct intratumoral injection of liposome-DNA to implanted hepatocellular carcinoma in nude mice led to a high level of transgene expression. 4 However, critical issues still exist in cationic liposome-mediated gene delivery to the liver.…”

Down‐regulation of fragile histidine triad expression in prostate carcinoma

“…The use of FHIT gene therapy also has been successful in initial attempts to treat lung carcinoma. Ramesh et al 52 used liposome vectors to deliver p53 and FHIT to localized primary lung carcinomas developed in mice. Significant suppression in primary and metastatic lung tumor growth was observed.…”

“…Taken together, these data suggest that loss of FHIT expression may be implicated in prostatic carcinogenesis, and FHIT may present as a potential target for future therapeutic intervention. 19,49,51,52,55 …”