Js. Bishop et al., Antitumoral effect of a nonviral interleukin-2 gene therapy is enhanced bycombination with 5-fluorouracil, CANC GENE T, 7(8), 2000, pp. 1165-1171
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.