Antitumoral effect of a nonviral interleukin-2 gene therapy is enhanced bycombination with 5-fluorouracil

Using a novel cationic lipid delivery system consisting of N-[1-(2,3-dioleo yloxy)propyl]-N,N,N-trimethylammonium chloride and cholesterol, we delivere d murine interleukin-2 (IL-2) cDNA directly into an established murine rena l cell carcinoma (Renca). Production of IL-2 within the tumor induced rejec tion of established tumors (62% on average), whereas control plasmid had li ttle or no effect (17% on average). Surviving animals treated with IL-2:lip id were highly resistant to Renca rechallenge, but not to cross-challenge w ith a syngeneic mammary adenocarcinoma. Experiments on selectively immunosu ppressed animals indicated a requirement for CD8(+) T, natural killer, and polymorphonuclear cells. By contrast, depletion of CD4(+) T cells did not d isrupt the ability of Il-a:lipid to induce tumor rejection. A combination o f IL-2 gene therapy with 5-fluorouracil treatment increased the antitumoral efficacy and survival of mice bearing primary and metastatic Renca tumors (42% survival with IL-2:lipid compared with 94% survival with IL-2:lipid pl us 5-fluorouracil), These data indicate that rejection of primary and metas tatjc tumors can be achieved after intratumoral delivery of a nonviral IL-2 gene therapy, and is increased in combination with systemic delivery of a conventional chemotherapeutic agent.