Abstract

Astrocytomas and glioblastomas have been particularly difficult to treat and refractory to chemotherapy. However, significant evidence has been presented that demonstrates a decrease in astrocytoma cell proliferation subsequent to an increase in cAMP levels. The 1321N1 astrocytoma cell line, as well as other astrocytomas and glioblastomas, expresses β₂-adrenergic receptors (β₂-ARs) that are coupled to G_s activation and consequent cAMP production. Experiments were conducted to determine whether the β₂-AR agonist (R,R′)-fenoterol and other β₂-AR agonists could attenuate mitogenesis and, if so, by what mechanism. Receptor binding studies were conducted to characterize β₂-AR found in 1321N1 and U118 cell membranes. In addition, cells were incubated with (R,R′)-fenoterol and analogs to determine their ability to stimulate intracellular cAMP accumulation and inhibit [³H]thymidine incorporation into the cells. 1321N1 cells contain significant levels of β₂-AR as determined by receptor binding. (R,R′)-fenoterol and other β₂-AR agonists, as well as forskolin, stimulated cAMP accumulation in a dose-dependent manner. Accumulation of cAMP induced a decrease in [³H]thymidine incorporation. There was a correlation between concentration required to stimulate cAMP accumulation and inhibit [³H]thymidine incorporation. U118 cells have a reduced number of β₂-ARs and a concomitant reduction in the ability of β₂-AR agonists to inhibit cell proliferation. These studies demonstrate the efficacy of β₂-AR agonists for inhibition of growth of the astrocytoma cell lines. Because a significant portion of brain tumors contain β₂-ARs to a greater extent than whole brain, (R,R′)-fenoterol, or some analog, may be useful in the treatment of brain tumors after biopsy to determine β₂-AR expression.