High density oligonucleotide array analysis of interferon-alpha 2a sensitivity and transcriptional response in melanoma

Interferon alpha (IFN-alpha) represents an adjuvant therapy of proven effec tiveness in increasing disease-free interval and survival in subgroups of m elanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. Furthermore, naturally occurrin g insensitivity to IFN-alpha may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential res ponders have not been identified so far. To explore the molecular basis of IFN-alpha responsiveness, we analysed the expression pattern of about 7000 genes in IFN-alpha sensitive and resistant cell lines and we compared the t ranscription profiles of cells cultured in the presence or absence of the c ytokine using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction upon IFN-cx, treatment by standard BH-thymidine incorporation an d flowcytometry. The study of 4 sensitive and 2 resistant cell lines allowe d the identification of 4 genes (RCC1, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and 2 (SHB and PKC-zeta) preferentially expr essed in resistant cells. IFN-alpha stimulation resulted in the expression of a panel of 19 known inducible genes in sensitive but not in resistant ce lls. Moreover a group of 30 novel IFN-alpha inducible genes was identified. These data may provide a useful basis to develop diagnostic tools to selec t potential IFN-alpha responders eligible for treatment, while avoiding unn ecessary toxicity to non-responders. Furthermore. by extending the knowledg e of the polymorphic effects of IFN-alpha on gene expression, they offer no vel clues to the study of its pleiotropic toxicity. (C) 2001 Cancer Researc h Campaign http://www.bjcancer.com.