Type I consensus interferon (CIFN) gene transfer into human melanoma cellsup-regulates p53 and enhances cisplatin-induced apoptosis: implications for new therapeutic strategies with IFN-alpha
M. Mecchia et al., Type I consensus interferon (CIFN) gene transfer into human melanoma cellsup-regulates p53 and enhances cisplatin-induced apoptosis: implications for new therapeutic strategies with IFN-alpha, GENE THER, 7(2), 2000, pp. 167-179
In this study, we describe the effects produced by the retroviral transduct
ion of human type I consensus IFN (CIFN) coding sequence into the 8863 and
1B6 human melanoma cell lines, derived from a metastatic and a primary huma
n melanoma, respectively. Melanoma cell lines producing approximately 10(3)
IU/ml of IFN were obtained. Interestingly, cisplatin treatment of IFN-prod
ucing 8863 and 1B6 melanoma cells resulted in a three- to four-fold increas
e in the percentage of apoptotic cells with respect to similarly treated pa
rental or control-transduced cell cultures. A similar effect, although less
intense, was caused by cultivation of parental melanoma cells in the prese
nce of exogenous CIFN. The increased susceptibility of the IFN-producing me
lanoma cell lines to cisplatin-induced apoptosis was associated with an IFN
-dependent accumulation of p53, which also correlated with a decrease in Bc
l-2 expression. Addition of exogenous CIFN to parental melanoma cells resul
ted in similar although weaker modulations of p53 and Bcl-2 expression. Cis
platin administration to nude mice bearing 3-day-old IFN-producing 8863 tum
ors resulted in complete tumor regression, while only a partial tumor inhib
ition was observed upon cisplatin treatment of mice bearing parental or con
trol-transduced 8863 tumors. Starting the cisplatin treatment 7 days after
tumor cell injection still resulted in a stronger inhibition of tumor growt
h in the mice bearing IFN-producing 8863 tumors as compared with parental t
umor-bearing mice. A comparable therapeutic effect was obtained after repea
ted peritumoral administration of 10(3) IU of exogenous CIFN and cisplatin
treatment. Interestingly, a spontaneous tumor regression was observed in nu
de mice injected with IFN-producing 1B6 cells, in contrast to the progressi
ve tumor growth occurring in mice receiving a similar inoculum of the paren
tal or control-transduced 1B6 melanoma cells. Repeated peritumoral administ
ration of 10(3) IU of exogenous CIFN to mice bearing parental 1B6 tumors ca
used only a transient inhibition of tumor growth. These results indicate th
at type I IFN gene transfer is an effective approach for suppressing the tu
morigenic phenotype of human melanoma cells and for increasing the efficacy
of anticancer drugs. These observations together with our previous finding
s showing the importance of IFN-alpha-T cell interactions in the generation
of an antitumor response in mouse models, underline the interest of using
type I IFN in gene therapy strategies for the treatment of human melanoma.