Bestatin selectively suppresses the growth of leukemic stem/progenitor cells with BCR/ABL mRNA transcript in patients with chronic myelogeneous leukemia.
The in vitro effect of bestatin on Philadelphia (Ph) chromosome positive chronic myeloid leukemia (CML) was investigated using mature clonogenic cells and primitive stem cells derived from long-term culture-initiating cells (LTC-ICs). Individual colonies were grown in methycellulose culture (clonogenic cells) and after 5 weeks, LTC (colonies derived from LTC-ICs) were individually isolated. DNA isolated from these clonogenic colonies was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis to detect BCR/ABL mRNA transcripts b3a2 and b2a2. At the mature hematopoietic progenitor cell level, almost all (20/21) colonies, including both erythroid and myeloid progenitors, were leukemic, i.e. BCR/ABL mRNA positive. Although normal progenitors were able to grow in the presence of bestatin, even at the most primitive progenitor cell level (LTC-ICs), the number of leukemic clones gradually decreased. Furthermore, bestatin suppressed the outgrowth of leukemic clones more frequently than control LTC without any effect on the growth of normal clones. These results indicate that bestatin, at levels that can be obtained by per os administration clinically, suppresses only Ph-positive leukemic clones without affecting normal hematopoiesis. Based on these results, we suggest that bestatin has the potential to provide another treatment for patients with CML.
Fujisaki
Tomoaki
T
First Department of Internal Medicine, Faculty of Medicine, Cancer Center, Kyushu University, 812, Fukuoka, Japan. tfujisaki@matsuyama.jrc.or.jp
Otsuka
Teruhisa
T
Gondo
Hisashi
H
Okamura
Takashi
T
Niho
Yoshiyuki
Y
Ohhinata
Akira
A
Abe
Fuminori
F
D002452:Cell Count; D002478:Cells, Cultured; D002999:Clone Cells; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D017997:Leukotriene C4 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects*
D011480:Protease Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017997:Leukotriene C4; D016044:Fusion Proteins, bcr-abl; D007930:Leucine; C012211:ubenimex