9-(tetrahydro-2-furyl)-adenine and 4-(3-4-dibutoxybenzyl)-2-imidazolidinone

Intravesical bacillus Calmette-Guerin (BCG) is currently the therapy of choice for superficial bladder cancer with a 60-70% response rate. Induction of cytokine production (e.g. IL-6, etc.) by BCG has been found in patient's urine in vivo as well as bladder cancer cell lines. However, the signalling mechanisms are still unclear. In this study, we investigated the effect of BCG on cAMP production and its role in regulating interleukin-6 expression in the human bladder cancer cell line, MGH. After 1 hr exposure to BCG, IL-6 gene expression in MGH cells increased by 2.5-3-fold and cAMP production increased by 8-10-fold in a time- and dose-dependent manner. BCG-induced cAMP production was inhibited by both antifibronectin antibody and an adenylate cyclase inhibitor, SQ22536 in a dose-dependent way. In the presence of SQ22536, IL-6 expression in MGH cells was also greatly reduced. Furthermore, cAMP-dependent kinase inhibitors H7 and HA1004 also inhibited BCG-induced IL-6 expression in MGH, with HA1004 being much less effective than H7. Thus, BCG induces cAMP production and may regulate interleukin-6 expression partially via a cAMP-dependent pathway in human bladder cancer cells.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adenine; Antibodies; BCG Vaccine; Colforsin; Cyclic AMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Humans; Imidazoles; Interleukin-6; Isoquinolines; Phosphodiesterase Inhibitors; Protein Denaturation; RNA, Messenger; Signal Transduction; Sulfonamides; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms

Forskolin caused a concentration dependent relaxation of rabbit detrusor muscle strips. The relaxant effect of forskolin was potentiated by the cyclic AMP sensitive phosphodiesterase inhibitor, Ro20-1274. Pretreatment with the beta-adrenergic antagonist, propranolol, did not inhibit the relaxation of rabbit detrusor induced by forskolin, whereas the relaxation response to forskolin was inhibited in part by the adenylate cyclase inhibitor, SQ22536. Forskolin also increased cyclic AMP levels significantly in rabbit detrusor muscle. These data suggest that detrusor muscle relaxation by forskolin may be mediated by cyclic AMP and that forskolin may activate adenylate cyclase without stimulating beta-adrenergic receptors in detrusor muscle.

Topics: Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Colforsin; Cyclic AMP; Drug Synergism; Enzyme Activation; Imidazoles; Male; Muscle Contraction; Muscle, Smooth; Propranolol; Rabbits; Urinary Bladder