POTENT ANTILEUKEMIC ACTIVITY OF THE NOVEL AGENTS NORSEGOLINE AND DIBEZINE

We examined the effect of norsegoline, a natural marine product, and d ibezine, a synthetic product, on the survival of human myeloid progeni tor cells [colony-forming unit-cells (CFU-C)] from normal individuals and from 10 patients with Philadelphia-positive chronic myelogenous le ukemia (CML) in chronic phase and blastic crisis, We compared their ef fect to the effect of IFN-alpha. Norsegoline, dibezine, and IFN-alpha inhibited the proliferation of CFU-C in a dose-dependent manner, The n umber of CFU-C from bone marrow (BM) of five CML patients in chronic p hase 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 statistical ly lower (P < 0.05) than the number of CFU-C derived from normal indiv iduals, A 16-h drug exposure of CD34(+) cells isolated from the periph eral blood of three CML patients in blastic crisis and from BM of two patients in chronic phase resulted in a marked inhibition in the abili ty of the cells to proliferate in liquid culture and a reduction in CF U-C content, Using the fluorescent in situ hybridization technique, we evaluated detection of the BCR/ABL fusion product in the CD34(+) cell s, 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 signal s 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 peri pheral blood, respectively, Our data indicate that norsegoline and dib ezine have lit vitro an antileukemic effect against Philadelphia-posit ive cells and may be used in conjunction with currently available agen ts for ex vivo purging of BM and/or peripheral blood of CML patients i n conjunction with autologous bone marrow transplantation.