Theophylline administration markedly reduces hepatic and pulmonary implantation of B16-F10 melanoma cells in mice

Theophylline-treated B16-F10 melanoma cells show a lower experimental metas tatic potential in vivo. To identify the possible mechanism(s) involved and on the basis of previous reports, we tested the induction of apoptosis in B16-F10 cells. Fluorescence activated cell sorter (FACS) analysis and p53 o verexpression in theophylline-treated B16-F10 melanoma cells appeared to su ggest enhanced cell death by apoptosis. The in vivo effects of orally admin istered theophylline in mice were investigated using different treatment sc hedules in mice that had undergone hepatic or pulmonary colonization with t umour cells, Mice received theophylline in their drinking water according t o different protocols: (i) from 3 days before tumour cell inoculation until animal sacrifice ('early treatment'); (ii) from 3 days before until 3 days after tumour cell inoculation ('short treatment'); or (iii) from 3 days af ter tumour cell inoculation until animal sacrifice ('late treatment'). In t he 'early treatment' group, the number of melanoma foci was reduced by 92.3 % in the liver and 81.4% in the lung compared with control animals (P<0.001 ). In the 'short treatment' group, there was an 80.2% and 72.2% reduction i n liver and lung metastases, respectively (P< 0.001). In the 'late treatmen t' group, the inhibition of metastasis was 59.7% for liver and 45.3% for lu ng (P<0.005). Survival studies showed that 50% of the 'early' theophylline- treated animals died 33.2 +/- 2.0 days after intrasplenic injection (contro l group: 23.1 +/- 1.8 days; P<0.001) and 33.9 +/- 2.5 days after tail vein injection (control group: 24.1 +/- 1.4 days; P< 0.001). Taken together, the se observations provide useful information for the potential clinical appli cation of theophylline as a chemotherapeutic agent against malignant melano ma. (C) 2000 Lippincott Williams & Wilkins.