Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on 'in vitro' growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors.
Homoharringtonine (HHT) is a cephalotaxine alkaloid that showed clinical efficacy in the chronic phase of chronic myeloid leukemia (Ph1+CML). As a single agent, it resulted in effectively controlling leukocytosis and in producing sporadic karyotypic conversions; its clinical use in combination with interferon (IFN-alpha) for the treatment of CML could thus be considered. In this study we evaluated the growth inhibition and the induction of apoptosis determined by HHT alone and in combination with IFN-alpha and cytosine arabinoside (Ara-C) on normal and CML (both in chronic, CML-CP and in blastic phase; CML-BP) hematopoietic progenitors. HHT is able to determine a dose-dependent cell growth inhibition; evaluation of cytotoxic activity on semisolid cultures showed an activity significantly higher on CML-CP than on normal cells (P = 0.02 for HHT 50 ng/ml and P = 0.01 for HHT 200 ng/ml). HHT exerted a synergistic effect with IFN-alpha, Ara-C and IFN-alpha + Ara-C in inhibiting CML-CP colony growth; the same activity was demonstrated by the combination of HHT with Ara-C and by the triple combination, but not by HHT + IFN-alpha, on normal myeloid progenitors. The triple combination only was able to exert a synergistic effect in CML-BP. The induction of apoptosis resulted HHT dose-dependent in CML-CP and normals; at higher drug concentrations (100-200-1000 ng/ml), HHT induced a significant increase of apoptotic cells (for normals: P = 0.04, P = 0.02 and P = 0.04; for CML-CP: P = 0.01, P = 0.01 and P = 0.04, respectively); no significant changes were observed in CML-BP. In conclusion, the differences in cytotoxic effect and apoptosis induction observed, depending on the various phases of CML, add experimental evidence to the different clinical results between the chronic phase, where the clone is responsive to HHT, and the acute phase, where the drug is ineffective. The in vitro synergism of HHT with Ara-C and IFN-alpha in CML-CP suggests further evaluation in the clinical setting.
Visani
G
G
Institute of Hematology and Medical Oncology Seràgnoli, University of Bologna, Italy.
Russo
D
D
Ottaviani
E
E
Tosi
P
P
Damiani
D
D
Michelutti
A
A
Manfroi
S
S
Baccarani
M
M
Tura
S
S
D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis; D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000494:pharmacology*; D005260:Female; D006248:Harringtonines / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D000077863:Homoharringtonine; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008297:Male
D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D016898:Interferon-alpha; D003561:Cytarabine; D000077863:Homoharringtonine