Eilatin: a novel marine alkaloid inhibits in vitro proliferation of progenitor cells in chronic myeloid leukemia patients

Abstract

We examined the effect of Eilatin, a novel marine product, on the survival of human myeloid progenitor cells (CFU-C) isolated from normal individuals and from 12 patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase and blastic crisis. We compared its effect to the effect of interferon-alpha (IFN-alpha) and cytosine arabinoside (Ara-C). Eilatin, IFN-alpha, and Ara-C inhibited the proliferation of CFU-C from normal individuals and CML patients in a dose-dependent manner. The percent survival of colony-forming units from bone marrow (BM) of seven CML patients in chronic phase exposed for 16 hours to Eilatin (10(-7) and 10(-6) M), IFN-alpha (500 U/mL), or Ara-C (10(-9) M and 10(-8) M) was found to be statistically lower (p < 0.05) than the percent survival of myeloid progenitors from normal individuals. A 16-hour exposure of CD34+ cells isolated from peripheral blood (PB) of three CML patients in blastic crisis and from BM of two patients in chronic phase to Eilatin 10(-7) M, IFN-alpha 500 U/mL, Ara-C 10(-9) M resulted in a marked inhibition in the ability of the cells to proliferate in liquid culture and a reduction in CFU-C content. Using fluorescent in situ hybridization (FISH), we evaluated detection of the BCR/ABL fusion product in the CD34+ cells. All five patients were 100% Ph+ at diagnosis. BCR/ABL translocations were detected in 94.6 +/- 0.6% of CD34+ cells after growth in liquid culture for 7 days. The level of BCR/ABL fusion signals detected after exposure of CD34+ cells for 16 hours to Eilatin 10(-7) M, IFN-alpha 500 U/mL, or Ara-C 10(-9) M were 54.5 +/- 5%, 63.6 +/- 5%, and 70 +/- 4%, respectively (mean +/- SE, n = 5). Our data indicate that Eilatin, a substance isolated from the Red Sea purple tunicate Eudistoma sp., has an antileukemic effect against in vitro Ph+ cells and may be used in conjunction with currently available agents for ex vivo purging of BM and/or PB of CML patients in conjunction with autologous bone marrow transplantation.