Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zoledronic acid inhibits the prenylation of ras-related proteins downstream of bcr-abl and preclinical studies have shown augmentation of the inhibitory effects of imatinib in BCR-ABL expressing cells. A Phase I/II study was designed to assess the safety and efficacy of the addition of zoledronic acid to imatinib in patients with chronic myeloid leukaemia (CML) with a suboptimal response to imatinib alone. Ten patients with CML who had been treated with imatinib for at least 2 years and had achieved and maintained a complete haematological response were included. Zoledronic acid was administered intravenously on one occasion every 28 d. The initial dose of 4 mg was given for three consecutive months; in the absence of significant toxicity and/or response the dose was escalated to 8 mg for an additional 3 months. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts and bone marrow cytogenetics. Addition of zoledronic acid to imatinib caused no haematological toxicity. There were no grade III or IV non-haematological adverse effects. Grade I fatigue, hypocalcaemia and fever were common side effects. No responses were demonstrated after 6 months on the combination.
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PMID:Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: a phase I/II study in patients in complete haematological remission. 1742 38

Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 microg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib- or ZOL-treated animals relative to controls. However, micro-computed tomographic (microCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling.
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PMID:The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. 2022 61