Effect of imatinib on haematopoietic recovery following idarubicin exposure

Abstract

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. Doubletreated 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.

Fullerenol−Cytotoxic Conjugates for Cancer Chemotherapy

“…Interestingly, a very high doxorubicin accumulation was observed in the spleen of the free doxorubicin treated mice (Figure d). This was consistent with a significant loss of spleen weight (Figure c), and histopathological analysis confirmed lymphocyte depletion in the periarteriolar lymphoid sheaths, with shrinkage of both the medulla and marginal zones of secondary follicles (Supporting Information, Figure 2) typical of doxorubicin-induced hematopoietic toxicity. , Furthermore, treatment with doxorubicin also resulted in significant loss of cardiac mass, consistent with cardiotoxicity reported with doxorubicin treatment . Interestingly, significantly elevated levels of doxorubicin were observed in the tumor following treatment with fullerenol- or single-walled CNT-conjugated doxorubicin as compared with free doxorubicin (Figure d).…”

Combined effects of doxorubicin and STI571 on growth, differentiation and apoptosis of CML cell line K562.

“…Based on already published results, cardiotoxicity or neutropenia should be taken into account when STI571 and DOX are considered in combined treatment. In mice treated with STI571 in combination with idarubicin, another anthracycline derivative, a more severe neutropenia was induced when compared with that of mice treated with idarubicin alone (Ruchatz et al, 2003). It is well known that cardiomyopathy and congestive heart failure could be developed after completion of cumulative anthracycline regimens (Steinherz et al, 1991).…”

Imatinib mesylate inhibits STAT5 phosphorylation in response to IL-7 and promotes T cell lymphopenia in chronic myelogenous leukemia patients

“…Despite the relatively high specificity of IM treatment towards the BCR-ABL fusion protein, off-target multikinase inhibitory effects occur and can interfere with normal hematopoiesis. 1, 2 For instance, non-specific inhibition of Flt3L has been associated with disruption of dendritic cell (DC) homeostasis and functions in both mice and humans. 3 In addition, studies have reported an interference of IM with T cell counts and activation.…”