The diverse effect of topoisomerase I specific inhibitor (camptothecin) on normal and BCR/ABL-dependent hematopoietic cells proliferation: therapeutic implications.
Camptothecin (CPT), a specific topoisomerase I inhibitor, in the presence of hematopoietic growth factors exerted an antiproliferative effect against normal bone marrow cells (NBMC) as well as chronic myelogenous leukemia-chronic phase (CML-CP) and blast crisis (CML-BC) cells. In the absence of growth factors, however, only the colony formation by CML-BC cells was inhibited by CPT, leaving NBMC and CML-CP cells intact or much less affected. Analysis of the cellular DNA content revealed that CPT induced specific changes in cell cycle distribution: decrease in S and G2/M fraction with simultaneous accumulation of the cells in G1 phase and the appearance of "sub-diploid" (apoptotic) peak. To determine if CPT is able to exert selective antileukemic effect, 1:1 mixture of NBMC and CML-BC cells was exposed to CPT in the absence of growth factors and assayed for growth ability in clonogenic assay and for expression of BCR/ABL transcript in single colonies. BCR/ABL transcript was not detected in colonies incubated with CTP, in contrast, most of colonies arising from untreated cells possessed leukemic origin (BCR/ABL expression). Our results indicate that CPT is selectively effective in vitro against the leukemia cells. This offers the prospect of a novel and more selective treatment of CML.
Fertała
J
J
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, USA.
Nieborowska-Skórska
M
M
Calabretta
B
B
Skórski
T
T
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001854:Bone Marrow Cells; D002166:Camptothecin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology*; D006397:Hematinics / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000032:analysis; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D006397:Hematinics; D012334:RNA, Neoplasm; D059004:Topoisomerase I Inhibitors; D016044:Fusion Proteins, bcr-abl; D002166:Camptothecin