The role of growth factors in the activity of pharmacological differentiation agents.
Bryostatin-1 inhibits acute myeloid leukemia (AML) in vitroat doses that stimulate the growth of normal hematopoietic progenitors.Although bryostatin-1 has a number of distinct biological activities, those specifically responsible for its antileukemic activity are unclear. We found that bryostatin-1 (10(-8) M) inhibited cell cycling at G(1), induced phenotypic evidence of differentiation, and limited the clonogenic growth of both AML cell lines and patient specimens. This activity was markedly enhanced by granulocyte/macrophage-colony stimulating factor, whereas growth factor-neutralizing antibodies completely inhibited both the differentiating and antileukemic activities of bryostatin-1. Cell cycle inhibition and growth factors were also required for the differentiating activities of two unrelated agents, hydroxyurea and phenylbutyrate. These data suggest that many pharmacological differentiating agents require both cell cycle arrest and lineage-specific growth factors for full activity and may explain why these agents have demonstrated only limited clinical efficacy.
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, Maryland 21231, USA.
William H
WH
Matsui
Douglas E
DE
Gladstone
Milada S
MS
Vala
James P
JP
Barber
Robert A
RA
Brodsky
B Douglas
BD
Smith
Richard J
RJ
Jones
D000208:Acute Disease; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D054713:Bryostatins; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D004338:Drug Combinations; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy; D018942:Macrolides; D010654:Phenylbutyrates / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D015703:Antigens, CD; D000970:Antineoplastic Agents; D054713:Bryostatins; D004338:Drug Combinations; D007783:Lactones; D018942:Macrolides; D010654:Phenylbutyrates; C046785:bryostatin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006918:Hydroxyurea