Differential protection of normal and malignant human myeloid progenitors (CFU-GM) from Ara-C toxicity using cycloheximide.
Cycloheximide, a reversible protein synthesis inhibitor, is thought to block DNA replication in normal cells by preventing synthesis of a labile protein. In animal systems, cycloheximide protects normal cells from cytotoxic S-phase specific agents, such as cytosine arabinoside (Ara-C). Malignant cells appear not to be susceptible to cycloheximide-induced cycle arrest and, subsequently, may not be protected from Ara-C cytotoxicity. The effect of cycloheximide on granulocyte/macrophage progenitors (CFU-GM) after in vitro Ara-C exposure was examined using normal human bone marrow, malignant progenitors from patients with chronic myelogenous leukemia (CML), and clonogenic cells from the human acute nonlymphocytic leukemia cell lines HL-60 and KG-1. Mononuclear or clonogenic cells were incubated for one hour with cycloheximide, followed by the addition, for three or 17 hours, of Ara-C before being plated in a methylcellulose culture system. CFU-GM survival was significantly increase if normal cells were treated with cycloheximide before Ara-C exposure. Similar cycloheximide pretreatment of CML progenitors and clonogenic HL-60 and KG-1 cells failed to protect CFU-GM from Ara-C-induced cytotoxicity.
D051777:AraC Transcription Factor; D001426:Bacterial Proteins; D001854:Bone Marrow Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000097:blood; D015470:Leukemia, Myeloid, Acute / Q000097:blood; D009000:Monocytes / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D012097:Repressor Proteins / Q000633:toxicity; D013997:Time Factors; D014157:Transcription Factors
D051777:AraC Transcription Factor; D001426:Bacterial Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D003513:Cycloheximide