Interferon-α and -γ in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines

Abstract

Mesothelioma is a tumor of the serous surfaces in the thorax and abdomen. This tumor has proved to be exceptionally resistant to treatment, although a variety of multi-modality therapies have been tried. We have used four human mesothelioma cell lines, originating from diffuse asbestos-related malignant (pleural) mesothelioma, to assess in vitro sensitivity to five chemotherapeutic drugs, to recombinant human interferon (IFN)-α and -γ and to combined immuno-chemotherapy. The cytotoxic effects were assayed by vital dye exclusion. The drugs tested were etoposide, cisplatin, mitoxantrone, 4-epirubicin and vindesine. The combinations tested were etoposide + cisplatin, and etoposide + cisplatin + mitoxantrone. All the drugs and combinations were also tested with recombinant human (rHu) IFN-α2C (rHulFN-α), rHulFN-γ, and rHulFN-α + rHulFN-γ. The cell lines were most sensitive to mitoxantrone, 4-epirubicin and vindesine (TC50 ≤ 0.001 μ/ml), and least sensitive to etoposide and cisplatin (TC50 ≥ 0.1 μg/ml) used singly. There was no Improvement in sensitivity when the drugs were combined. To further investigate the lack of response to cisplatin treatment, we examined the binding of cisplatin to the mesothelioma cell DNA. The tumor cell DNA bound markedly less cisplatin than human fetal fibroblast DNA. Three cell lines were tested with rHulFN-α and rHulFN-γ their own or rHulFN-α + rHulFN-γ. They were consistently sensitive to rHulFN-α, but the sensitivity to rHulFN-γ varied with the cell lines. Finally, we tested two cell lines with the drugs singly and in combination, together with 0.01 μg/ml each of rHulFN-α and rHulFN-γ. The growth Inhibitory effects of all the individual drugs and combinations were improved by the addition of rHulFN-α and rHulFN-γ, by as much as 30% in some cases. We conclude that mitoxantrone and 4-epirubicin each combined with IFN should be further investigated in the development of mesothelioma therapy.