REDUCED DNA-SYNTHESIS AND CELL VIABILITY IN SMALL-CELL LUNG-CARCINOMABY TREATMENT WITH CYCLIC-AMP PHOSPHODIESTERASE INHIBITORS

This study investigated the effects of the adenosine 3',5'-cyclic mono phosphate (cAMP) phosphodiesterase inhibitors caffeine, theophylline, and 3-isobutyl-1-methyl-xanthine (IBMX) on the proliferation and viabi lity of the small cell lung carcinoma (SCLC) cell lines NCI-H345, NCI- H128, and SCC-9. These effects were correlated with the ability of the drugs to induce intracellular Ca2+ mobilization. Treatment of NCI-H34 5 cells with caffeine resulted in rapid mobilization of Ca2+, as indic ated by Fura-2 fluorescence. Incubation of NCI-H345 cells with 6.25 mM caffeine resulted in a 62% inhibition of [H-3]thymidine uptake after 2 hr, indicating reduced DNA synthesis. Incubation with 25 mM caffeine resulted in almost total inhibition of [H-3]thymidine uptake after 2 hr. Similar effects on [H-3]thymidine uptake were seen upon treatment of NCI-H128 and SCC-9 cells with caffeine; however, these cells did no t exhibit caffeine-induced Ca2+ mobilization. Inhibition of DNA synthe sis (66-93%) also occurred upon incubation of all cell lines with theo phylline and IBMX, which did not mobilize Ca2+. Treatment of NCI-H345, NCI-H128, and SCC-9 cells with caffeine, theophylline, or IBMX marked ly reduced cell viability. Levels of cAMP increased in the cells follo wing treatment with caffeine, theophylline, or IBMX, reflecting the ab ility of these drugs to inhibit cAMP phosphodiesterase. These results suggest that the decrease in DNA synthesis and the subsequent cell dea th induced by these drugs are due to reduced cAMP phosphodiesterase ac tivity, rather than to changes in intracellular Ca2+. These findings i ndicate that drugs that alter cAMP signaling pathways are potentially valuable agents to inhibit SCLC survival. (C) 1998 Elsevier Science In c.