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Further characterization of the leukemogenic activity of haloperidol in mice
1Academy of Sciences of the German Democratic Republic, Central Institute of Cancer Research, Berlin.
Abstract:
Haloperidol, a butyrophenon, is widely used for the treatment of psychotic disorders in man. Recently we reported that this drug causes, with high incidence, the development of monocytic-myeloid leukemias in male NMRI mice upon 5 X 5 mg/kg i.p. administration. Here we present evidence for the leukemogenic effect of haloperidol in two other strains of mice (XVII AKF1 hybrids, and the low leukemic BALB/c/BOM). The strain-dependent incidence of leukemias ranged both in males and females between 34% (AKR) and 69% (XVII AKF1) with average latencies between approximately 200 (AKR) and 600 (BALB/c) days. On the basis of cytological and cytochemical criteria the predominating type of leukemias was classified as monocytic-myeloid. These leukemic were serially transplantable. Cell-free extracts of leukemic tissues did not induce the disease indicating that no virus was activated by haloperidol. However, when the drug was administered to AKR mice after a suboptimal dose of nitrosomethylurea (NMU), a higher incidence of mixed-type leukemias was observed as with haloperidol alone. NMU alone induced lymphatic leukemias with proven viral involvement. The tumor promoter 12-0-tetradecanoylphorbol-13-acetate did not influence haloperidol-induced leukemogenesis.
Insights
The antipsychotic drug haloperidol induces monocytic-myeloid leukemias in mice across different strains. This effect is strain-dependent and not caused by viral activation, but can be enhanced by nitrosomethylurea.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- Haloperidol is a widely used antipsychotic medication.
- Previous studies indicated haloperidol induces myeloid leukemias in male NMRI mice.
Purpose of the Study:
- To investigate the leukemogenic effect of haloperidol in different mouse strains.
- To characterize the type of leukemia induced by haloperidol.
- To explore potential mechanisms of haloperidol-induced leukemogenesis.
Main Methods:
- Administration of haloperidol to various mouse strains (XVII AKF1, BALB/c/BOM, AKR).
- Monitoring for leukemia development and calculating incidence and latency periods.
- Cytological and cytochemical analysis of leukemic cells.
- Testing for viral involvement using cell-free extracts.
- Investigating combined effects with nitrosomethylurea (NMU) and a tumor promoter.
Main Results:
- Haloperidol induced monocytic-myeloid leukemias in multiple mouse strains with varying incidence (34%-69%) and latencies (200-600 days).
- The induced leukemias were serially transplantable.
- No evidence of viral activation was found.
- Co-administration with NMU increased mixed-type leukemia incidence, while a tumor promoter had no effect.
Conclusions:
- Haloperidol exhibits a strain-dependent leukemogenic potential in mice.
- The mechanism appears non-viral.
- Haloperidol may act as a co-carcinogen, particularly when combined with agents like NMU.
