Growth inhibition of subcutaneous mouse melanoma and induction of natural killer cells by liposome-mediated interferon-beta gene therapy.
In this study we investigated the antitumour effect and mechanism of action of cationic liposome-mediated murine interferon-beta (IFNbeta) gene therapy in mouse B16F1 melanoma cells in vitro and in vivo. Murine IFNbeta gene transfer by cationic liposome resulted in substantial growth inhibition of B16F1 melanoma cells in culture when compared with phosphate buffered saline or recombinant murine IFNbeta treatment, or lacZ control gene transfer. Use of video-enhanced contrast-differential interference contrast (VEC-DIC) microscopy revealed that liposomes containing the murine IFNbeta gene [lip(pSV2muIFNbeta)], but not recombinant murine IFNbeta, induced dramatic morphological changes that characterize apoptosis, including bleb formation, shrinkage of cells, nuclear condensation and 'ballooning', in approximately 30% of the cells treated. Intratumoral administration of lip(pSV2muIFNbeta) resulted in a 5.5-fold reduction in the mean volume of subcutaneous melanoma lesions in syngeneic mice 15 days after treatment and eradicated the tumour in 18% of the mice treated. Immunocytochemical analysis demonstrated that a larger number of natural killer (NK) cells infiltrated the tumour following lip(pSV2muIFNbeta) treatment than in controls. In vivo depletion of NK cells using the anti-asialoGM1 antibody reduced the efficacy of lip(pSV2muIFNbeta) treatment. Taken together, our data suggest that cationic liposome-mediated IFNbeta gene therapy could be effective against melanoma by directly inducing cell death and stimulating NK cells.
Ryuke
Yasushi
Y
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mizuno
Masaaki
M
Natsume
Atsushi
A
Suzuki
Osamu
O
Nobayashi
Misato
M
Kageshita
Toshiro
T
Matsumoto
Kazuhiko
K
Saida
Toshiaki
T
Yoshida
Jun
J
D000818:Animals; D002412:Cations; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D016899:Interferon-beta / Q000008:administration & dosage* / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology; D008081:Liposomes; D008213:Lymphocyte Activation / Q000502:physiology; D008546:Melanoma, Experimental / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D014162:Transfection
D002412:Cations; D008081:Liposomes; D016899:Interferon-beta