Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts

The use of cationic liposomes as nonviral vehicles for the delivery of ther apeutic molecules is becoming increasingly prevalent in the field of gene t herapy. We have: previously demonstrated that the use of the transferrin li gand (Tf) to target a cationic liposome delivery system resulted in a signi ficant increase in the transfection efficiency of the complex [Xu, L., Piro llo, K.F., and Chang, E.H. (1997), Hum. Gene Ther. 8, 467-475]. Delivery of wild-type (wt) p53 to a radiation-resistant squamous cell carcinoma of the head and neck (SCCHN) cell line via this ligand-targeted, liposome-complex was also able to revert the radiation resistant phenotype of these cells i n vitro. Here we optimized the Tf/liposome/DNA ratio of the complex (LipT) for maximum tumor cell targeting, even in the presence of serum. The effici ent reestablishment of wtp53 function in these SCCHN tumor cells in vitro, via the LipT complex, restored the apoptotic pathway, resulting in a signif icant increase in radiation-induced apoptosis that was directly proportiona l to the level of exogenous wtp53 in the tumor cells. More significantly, i ntravenous administration of LipT-p53 markedly sensitized established SCCHN nude mouse xenograft tumors to radiotherapy. The combination of systemic L ipT-p53 gene therapy and radiation resulted in complete tumor regression an d inhibition of their recurrence even 6 months after the end of all treatme nt. These results indicate that this tumor-specific, ligand-liposome delive ry system for p53 gene therapy, when used in concert with conventional radi otherapy, can provide a new and more effective means of cancer treatment.