Antitumoral effect of a nonviral interleukin-2 gene therapy is enhanced by combination with 5-fluorouracil.
Using a novel cationic lipid delivery system consisting of N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride and cholesterol, we delivered murine interleukin-2 (IL-2) cDNA directly into an established murine renal cell carcinoma (Renca). Production of IL-2 within the tumor induced rejection of established tumors (62% on average), whereas control plasmid had little or no effect (17% on average). Surviving animals treated with IL-2:lipid were highly resistant to Renca rechallenge, but not to cross-challenge with a syngeneic mammary adenocarcinoma. Experiments on selectively immunosuppressed animals indicated a requirement for CD8+ T, natural killer, and polymorphonuclear cells. By contrast, depletion of CD4+ T cells did not disrupt the ability of IL-2:lipid to induce tumor rejection. A combination of 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 plus 5-fluorouracil). These data indicate that rejection of primary and metastatic 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.
Bishop
J S
JS
Valentis, Inc., The Woodlands, Texas 77381-4248, USA.
Thull
N M
NM
Matar
M
M
Quezada
A
A
Munger
W E
WE
Batten
T L
TL
Muller
S
S
Pericle
F
F
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D003131:Combined Modality Therapy; D018076:DNA, Complementary / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D015316:Genetic Therapy; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage
D018076:DNA, Complementary; D007376:Interleukin-2; D000644:Quaternary Ammonium Compounds; C054005:N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium; D005472:Fluorouracil