Further studies on mechanisms of abnormal prostaglandin response by chronic myelogenous leukaemia granulocyte/macrophage progenitors.
Prostaglandins of the E series (PGE) have varying effects in vitro on normal granulocyte/macrophage (CFU-GM) progenitors. When added directly to cultures, PGE inhibits growth of normal 7 and 14 day bone marrow CFU-GM in a dose-dependent manner, while CML CFU-GM are refractory to PGE inhibition. The plant diterpene forskalin, a potent activator of intracellular cyclic AMP, inhibited normal and CML CFU-GM, indicating that the response of CML cells to increased intracellular cyclic AMP is normal. Low dose forskalin, which potentiates activators of adenyl cyclase, showed additive effects with PGE on normal CFU-GM cells, however, showed no additive effects of PGE and forskalin, suggesting that PGE failed to activate adenyl cyclase. Normal CFU-GM incubated with PGE for two hours showed a significant increase in CFU-GM growth, and removal of adherent cells prior to exposure to PGE abrogated this effect. CML cells did not respond to a 2-h exposure to PGE, and removal of adherent cells from these cultures had no effect. Normal and CML CFU-GM showed dose-dependent increases in proliferation in the presence of PGF2. These studies confirm that CML CFC-GM are refractory to inhibition by PGE, and show that these cells respond normally to increased levels of intracellular cyclic AMP. Response of CML cells to PGF2 alpha is normal, and conversion of PGE to PGF could result in increased granulocyte progenitor proliferation.
D000262:Adenylyl Cyclases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D005576:Colforsin; D004224:Diterpenes / Q000494:pharmacology; D006098:Granulocytes / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000503:physiopathology*; D008264:Macrophages / Q000502:physiology*; D011458:Prostaglandins E / Q000494:pharmacology*
D004224:Diterpenes; D011458:Prostaglandins E; D005576:Colforsin; D000262:Adenylyl Cyclases