In vitro effect of clozapine on hemopoietic progenitor cells.
OBJECTIVE
Clozapine is a diabenzodiazepine derivative characterized by a high therapeutic index in schizophrenic patients resistant to traditional neuroleptic drugs, because of the rarity of any extrapyramidal side effects, and its particular hematologic toxicity. According to the international literature, clozapine-induced neutropenia occurs mainly during the first 4-6 months of treatment, and its incidence decreases considerably over time. This neutropenic effect is not dose-dependent and normally clears up after drug discontinuation, although it may evolve into agranulocytosis. The aim of this study is to evaluate the in vitro toxic effect of clozapine and N-desmethylclozapine on both committed and immature human hematopoietic progenitor cells.


METHODS
Cytotoxic assays were performed in vitro on normal human bone marrow samples treated with clozapine or with its metabolite N-desmethylclozapine. The clonogenic potential after treatment with both compounds was assessed on low density mononuclear cells (LD-MNC), purified CD34+ cells, cytokine driven liquid cultures and long term culture initiating cell (LTC-IC).


RESULTS
Clozapine and N-desmethylclozapine had a dose-dependent inhibitory effect on in vitro growth of CFU-GM and BFU-E from normal bone marrow. The two drugs had toxic effects on purified CD34+ progenitor cells but no significant effect on LTI-IC.


CONCLUSIONS
Our data indicate a cytotoxic effect, which is more pronounced with N-desmethylclozapine and at high doses, on the committed progenitor cell compartment but not on primitive hematopoietic cells. Furthermore, our data show that clozapine and N-desmethylclozapine have a direct effect on treated cells and do not induce apoptotic death.
Deliliers
G L
GL
Istituto di Scienze Mediche, Ospedale Maggiore I.R.C.C.S., University of Milan, Fondazione Matarelli, Italy. lambert@imiucca.csi.unimi.it
Servida
F
F
Lamorte
G
G
Quirici
N
N
Soligo
D
D
D014150:Antipsychotic Agents / Q000009:adverse effects / Q000633:toxicity*; D002478:Cells, Cultured; D003024:Clozapine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine