Receptor-mediated antiproliferative effects of corticosteroids in Lewis lung tumors

Abstract

Dextran-coated charcoal competitive binding assays and Scatchard analysis revealed the presence of high-affinity, low capacity binding sites for dexamethasone in cytosol preparations from Lewis lung tumors. In vitro studies with live cells indicated approximately 9000 nuclear binding sites/cell for the ligand-receptor complex. In vivo inhibition of cell proliferation by dexamethasone, methylprednisolone and triamcinolone acetonide was found to be dose-dependent. Changes in the [³H]-TdR labeling index, mitotic index and saturable cytosol receptor sites after dexamethasone treatment in vivo suggested a dose-dependent G₁ progression delay which, after cessation of dexamethasone treatments, was apparently reversible. Resumption of cell-cycle progression was characterized by synchronous progression through S-phase and correlated temporally with receptor site desaturation. In vivo studies indicated that the effectiveness of vincristine given after dexamethasone was highly sequence-dependent, with the most effective sequence interval being coincident with the interval of maximal S-phase cellularity. Other studies indicated sequential chemotherapy with dexamethasone, vincristine and 5-Fu could be effectively employed, following primary tumor excision, to increase animal survival.