Effect of imatinib on haematopoietic recovery following idarubicin exposure.
SCF is a potent pro-proliferative cytokine crucial for haematopoiesis, which binds to c-kit and activates its tyrosine kinase activity. Inactivating mutations of either SCF or c-kit have been described in mice and lead to increased sensitivity to treatment with ionising radiation. Imatinib is a tyrosine kinase inhibitor with high affinity for c-Abl, PDGFR and c-kit. In this study we investigated the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. Our results indicate that the simultaneous administration of imatinib enhances idarubicin-induced haematopoietic toxicity in vivo and in vitro.
Ruchatz
H
H
Department of Experimental Oncology, The National Cancer Institute, Milan, Italy.
Puttini
M
M
Cleris
L
L
Pilotti
S
S
Gambacorti-Passerini
C
C
Formelli
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001549:Benzamides; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D015255:Idarubicin / Q000008:administration & dosage / Q000633:toxicity*; D000068877:Imatinib Mesylate; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D015431:Weight Loss
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D015255:Idarubicin