ANTI-INVASIVE EFFECTS OF THEOPHYLLINE ON EXPERIMENTAL B16-F10 MELANOMA LUNG METASTASIS

Background - The effect of methylxanthines on tumors has been well doc umented, but little is known about their influence on cancer metastasi s. The ability of theophylline and caffeine to inhibit lung metastasis of melanoma was studied. Methods - B16-F10 murine melanoma cells were cultured with 1 mM theophylline or caffeine for 72h and the different groups of in-vitro-treated cells were injected i.v. into C57BL/6 mice for lung metastasis evaluation. A novel densitometric analysis was ap plied to histological sections of colonized lungs. By this procedure, the total number of melanoma foci and their average size were estimate d. Results - Our data showed a similar theophylline-induced decrease o f the proliferation (71% reduction, p<0.01) and invasive (67% reductio n, p<0.01) rate, whereas caffeine treatment affected the proliferation (62% reduction, p<0.01) more than the invasion (25% reduction, p<0.01 ). Preliminary in-vitro experiments performed on B16-F10 cells, in an attempt to identify the metastatic step affected by theophylline and c affeine, showed an inhibition of both their adhesiveness to laminin an d collagen type IV and their migration through Matrigel. Conclusions - These data not only confirm the previously observed antiproliferative effect of theophylline and caffeine on tumor cells, but for the first time demonstrate that the antineoplastic property of theopylline is p otentiated by a remarkable anti-invasive action.