ABSTRACT
The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [(125)I] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo.
Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , ATP-Binding Cassette Transporters/metabolism , Drug Resistance, Neoplasm , Hematopoietic Stem Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Piperazines/pharmacokinetics , Pyrimidines/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Animals , Antineoplastic Agents/pharmacokinetics , Benzamides , Binding Sites , Humans , Imatinib Mesylate , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Neoplasm Proteins/genetics , Protein Kinase Inhibitors , Recurrence , Transduction, GeneticABSTRACT
Pulmonary infarction and hemorrhage are important differential diagnoses in pulmonary coin lesions, especially in patients with underlying hematologic malignancies. We report a 58-year-old female patient suffering from polycythemia vera presenting with multiple pulmonary coin lesions. Open lung biopsy and subsequent histologic investigations showed organized pulmonary infarction and primary pulmonary thrombotic arteriopathy. Although histologic features are non-contributory in distinguishing organized thrombosis from organized thromboembolism, the clinical setting and localization of the lesions suggest that in the present case the vascular lesions are due to organized thrombosis.
Subject(s)
Polycythemia Vera/complications , Pulmonary Artery/pathology , Pulmonary Embolism/etiology , Solitary Pulmonary Nodule/etiology , Biopsy/methods , Diagnosis, Differential , Female , Humans , Lung/blood supply , Lung/diagnostic imaging , Lung/pathology , Middle Aged , Polycythemia Vera/pathology , Pulmonary Embolism/diagnosis , Solitary Pulmonary Nodule/pathology , Tomography, X-Ray ComputedABSTRACT
Although the local anaesthetic prilocaine is less cardio- and neurotoxic than lidocaine, it bears the disadvantage of the formation of methaemoglobin by the metabolite o-toluidine. Prilocaine is often successfully used, especially for the blockade of the brachial plexus, but one problem of this technique is the failure rate of 3-10%, with the consequence that general anaesthesia after administration of prilocaine is frequently necessary. Methaemoglobin formation after prilocaine administration has been thoroughly investigated. Nothing is known, however, about the interactions of prilocaine and the induction of general anaesthesia relative to methaemoglobinaemia. CASE REPORT. Two patients (47 and 52 years old) each received 500 mg prilocaine for the axillary blockade of the brachial plexus. After 100 and 120 min respectively, it was necessary to induce general anaesthesia, for which 350 mg thiopental, 1 mg alfentanil and 45 mg atracurium were used. At 15 min after induction, methaemoglobin levels had increased by 70% and 25%, respectively, from baseline before general anaesthesia. CONCLUSION. It is not possible to explain these findings conclusively with the present method. To check whether displacement of o-toluidine from the plasma protein binding might have been responsible, we provoked methaemoglobinaemia in vitro by adding o-toluidine to heparinised blood. Thiopental was then added to half the specimens. Subsequently, methaemoglobin levels were lower in the samples with thiopental. Three explanations seem plausible: (1) Thiopental blocks the hydroxylase of the endoplasmic reticulum, with the result that o-toluidine cannot be further metabolised, leading to higher o-toluidine and methaemoglobin levels. (2) Isoflurane improves the blood supply of the liver. This results in increased metabolism of prilocaine to o-toluidine. (3) The results were accidental. To clarify which of these explanations is correct, further investigation is necessary.
