Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo

Abstract

Lung cancer is one of the leading causes of death in the world. The underlying cause for lung cancer has been attributed to various factors that include alteration and mutation in the tumor suppressor genes. Restoration of normal function of the tumor suppressor gene is a potential therapeutic strategy. Recent studies have identified a group of candidate tumor suppressor genes on human chromosome 3p21.3 that are frequently deleted in human lung and breast cancers. Among the various genes identified in the 3p21.3 region, we tested the antitumor activity of the FUS1 gene in two human non-small-cell lung cancer (NSCLC) xenografts in vivo. Intratumoral administration of FUS1 gene complexed to DOTAP:cholesterol (DOTAP:Chol) liposome into subcutaneous H1299 and A549 lung tumor xenograft resulted in significant (P ¼ .02) inhibition of tumor growth. Furthermore, intravenous injections of DOTAP:Chol-FUS1 complex into mice bearing experimental A549 lung metastasis demonstrated significant (P ¼ .001) decrease in the number of metastatic tumor nodules. Finally, lung tumor-bearing animals when treated with DOTAP:Chol-FUS1 complex demonstrate prolonged survival (median survival time: 80 days, P ¼ .01) compared to control animals. This result demonstrates the potent tumor suppressive activity of the FUS1 gene and is a promising therapeutic agent for treatment of primary and disseminated human lung cancer.

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…On the basis of these findings re-introduction of FUS1 has entered phase I/II clinical trials for lung cancer using a nonviral nanoparticle-based systemic gene therapy. Using this method FUS1 does inhibit lung tumour xenograft growth in mice, reduces metastases and prolongs survival, however, this nanoparticle-based systemic therapy is problematic at present due to inflammatory responses Ito et al, 2004). Myristoylation was found to be essential for FUS1-mediated tumour suppression in vitro and in vivo (Uno et al, 2004).…”

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression: inhibition of c-Abl by the tumor suppressor gene product Fus1

“…96th Annual American Association for Cancer Research, April 2005). Of note, both the A549 and H1299 NSCLC cell lines are known have the 3p21.3 deletion and are deficient in the Fus1 protein (Kondo et al, 2001;Ito et al, 2004).…”

Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

“…14,15 We have previously demonstrated that the forced expression of wild-type (wt)-FUS1 significantly inhibited tumor cell growth by induction of apoptosis and alteration of cellcycle kinetics in 3p21.3-deficient NSCLC cells in vitro, and efficiently suppressed tumor growth and metastasis in mouse models of human lung cancer. 15,16 Molecular therapy by introduction of the TSGs, such as p53, into tumors has shown the potential to restore sensitivities to chemotherapy in primary lung cancers that lack p53 function. [17][18][19][20][21][22][23] However, no information has been available about the combined effects of exogenous expression of FUS1 tumor suppressor with any of various chemotherapeutic drugs on tumor suppression activity.…”