Potent antileukemic activity of the novel agents norsegoline and dibezine.
We examined the effect of norsegoline, a natural marine product, and dibezine, a synthetic product, on the survival of human myeloid progenitor cells [colony-forming unit-cells (CFU-C)] from normal individuals and from 10 patients with Philadelphia-positive chronic myelogenous leukemia (CML) in chronic phase and blastic crisis. We compared their effect to the effect of IFN-alpha. Norsegoline, dibezine, and IFN-alpha inhibited the proliferation of CFU-C in a dose-dependent manner. The number of CFU-C from bone marrow (BM) of five CML patients in chronic phase exposed for 16 h to norsegoline (10(-8)-10(-6)M), dibezine (10(-8)-10(-6)M), and IFN-alpha (500 units/ml) was found to be statistically lower (P < 0.05) than the number of CFU-C derived from normal individuals. A 16-h drug exposure of CD34(+) cells isolated from the peripheral blood of three CML patients in blastic crisis and from BM of two patients in chronic phase resulted in a marked inhibition in the ability of the cells to proliferate in liquid culture and a reduction in CFU-C content. Using the fluorescent in situ hybridization technique, we evaluated detection of the BCR/ABL fusion product in the CD34(+) cells. All five patients were 100% Philadelphia positive at diagnosis. BCR/ABL translocations were detected in 94.6 +/- 0.6% of cells following their growth in liquid culture for 7 days. Following exposure of CD34(+) cells to norsegoline, dibezine, or IFN-alpha, BCR/ABL fusion signals could be detected in 73 +/- 11%, 66.5 +/- 4. 7%, and 66.0 +/- 2.5% of cells from BM and 72.3 +/- 5%, 68.8 +/- 7%, and 60.6 +/- 6.8% of peripheral blood, respectively. Our data indicate that norsegoline and dibezine have in vitro an antileukemic effect against Philadelphia-positive cells and may be used in conjunction with currently available agents for ex vivo purging of BM and/or peripheral blood of CML patients in conjunction with autologous bone marrow transplantation.
Einat
M
M
Department of Cell Biology and Histology, Sackler School of Medicine and School of Chemistry, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, USA.
Nagler
A
A
Lishner
M
M
Amiel
A
A
Yarkoni
S
S
Rudi
A
A
Gellerman
G
G
Kashman
Y
Y
Fabian
I
I
D000293:Adolescent; D000328:Adult; D000470:Alkaloids / Q000633:toxicity*; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000633:toxicity*; D001752:Blast Crisis / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D002648:Child; D003114:Colony-Forming Units Assay; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000633:toxicity; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010619:Phenazines / Q000633:toxicity*
D000470:Alkaloids; D015703:Antigens, CD; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D016898:Interferon-alpha; D010619:Phenazines; C117149:dibezine; C117147:norsegoline