title: Hydrocortisone in culture protects the blast cells in acute myeloblastic leukemia from the lethal effects of cytosine arabinoside.
abstract: The blast cells in acute myeloblastic leukemia (AML) respond to many of the same regulatory mechanisms that control normal hemopoiesis. These include the growth factors that bind to membrane receptors and steroid hormones or vitamins that have intracellular receptors. We report the effects in culture of the steroid glucocorticoid hydrocortisone on freshly explanted AML blasts from patients and on two continuous AML cell lines. Only small changes in clonogenic cell numbers in suspension cultures were seen in the presence of hydrocortisone. The most striking effect of the hormone was on the sensitivity of blasts cells to cytosine arabinoside (ara-C). In contrast to the response of AML blast cells to retinoic acid, a ligand for intracellular steroid receptors that sensitizes some blast populations to ara-C, hydrocortisone reduced the toxic effects of the drug. The protective action of hydrocortisone was not mediated through the cell cycle since exposure of blasts to hydrocortisone did not affect the percentage of cells in DNA synthesis as measured with the tritiated thymidine (3HTdR) "suicide" technique. The hydrocortisone effect could be demonstrated using a pulse (20 min) exposure protocol. Blasts pulsed with increasing specific activities of 3HTdR showed the usual response pattern with an initial loss in plating efficiency to about 50% of control, followed by a plateau, regardless of whether the cells had been exposed to hydrocortisone. Control blasts exposed to increasing ara-C concentrations gave very similar dose-response curves; in striking contrast, blast cells cultured in hydrocortisone, then pulsed with ara-C did not lose colony-forming ability even though the same population was sensitive to 3HTdR. The hydrocortisone effect was dose and time related; protection from ara-C increased from 10(-8) to 10(-5) M and was seen after 4 hr exposure but required 8 hr to reach a maximum. We conclude that hydrocortisone can protect blasts from the lethal effects of ara-C even while the cells are in active DNA synthesis.
authors.affiliation: Ontario Cancer Institute, University of Toronto, Canada.
authors.forename: G S
authors.initials: GS
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Minkin
authors.forename: M D
authors.initials: MD
authors.lastname: Minden
authors.forename: E A
authors.initials: EA
authors.lastname: McCulloch
mesh_terms: D001752:Blast Crisis / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D003561:Cytarabine; D014316:Tritium; D004317:Doxorubicin; D004247:DNA; D013936:Thymidine; D006854:Hydrocortisone