How tyrosine kinase inhibitors impair metabolism and endocrine system function: A systematic updated review

Tyrosine kinase inhibitors (TKIs) advent has deeply changed the outcome of chronic myeloid leukemia (CML) patients, with improved rates of response and overall survival. However, for this success some patients paid the price of a number of peculiar side effects, the so-called off-target side effects, specific for each one TKI. These effects are due to non-selective inhibition of other tyrosine kinase receptors, such as PDGFR, c-KIT, Src, VEGF. Consequences of this inhibition, some metabolic changes during the treatment with TKIs are reported. Aim of present review is to report metabolic changes and potential mechanisms involved in the pathogenesis related to imatinib, second (nilotinib and dasatinib) and third generation (bosutinib and ponatinib) TKIs.     

Changes in pERK1/2 and pAKT expression in melanoma lesions after imatinib treatment

Response to treatment with imatinib mesylate has been associated in preclinical models with the inhibition of two signaling pathways that promote cellular survival - the phosphatidylinositol 3-kinase/AKT pathway and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway. We sought to evaluate the extent of inhibition of these two pathways in metastatic melanoma specimens from patients treated with imatinib. Metastatic melanoma tumor samples were obtained before and during the second week of imatinib treatment from patients enrolled in a phase II study. A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissues, and immunohistochemical analysis was performed using standard techniques to detect phosphorylated (p) ERK1/2 and pAKT expression. Of 21 patients who were treated with imatinib, tumor samples adequate for analysis were available both at baseline and during the second week of treatment from 10 patients for pERK1/2 expression and from nine patients for pAKT expression. No consistent pattern of change in pAKT or pERK expression after treatment with imatinib was observed. No apparent correlation between the clinical benefit of imatinib treatment and changes in pAKT and pERK1/2 expression was observed. A better understanding of the AKT and mitogen-activated protein kinase pathways is needed to optimize the clinical benefit of targeted therapy, such as imatinib.     

The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate

Purpose It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib. Methods The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4. Results In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either. Conclusion The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib. Roos L. Oostendorp, Serena Marchetti contributed equally to this article.     

BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by excessive granulopoiesis due to the formation of the constitutively active tyrosine kinase BCR-ABL. An effective drug against CML is imatinib mesylate, a tyrosine kinase inhibitor acting on Abl kinases, c-KIT, and platelet-derived growth factor receptor. Recently, a study revealed that patients treated with imatinib showed impaired CTL responses compared with patients treated with IFN-alpha, which might be due to a treatment-induced reduction in immunogenicity of CML cells or immunosuppressive effects. In our study, we found that inhibition of BCR-ABL leads to a down-regulation of immunogenic antigens on the CML cells in response to imatinib treatment, which results in the inhibition of CML-directed immune responses. By treating CML cells with imatinib, we could show that the resulting inhibition of BCR-ABL leads to a decreased expression of tumor antigens, including survivin, adipophilin, hTERT, WT-1, Bcl-x(L), and Bcl-2 in correlation to a decreased development of CML-specific CTLs. In contrast, this reduction in immunogenicity was not observed when a CML cell line resistant to the inhibitory effects of imatinib was used, but could be confirmed by transfection with specific small interfering RNA against BCR-ABL or imatinib treatment of primary CML cells.     

Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance.

Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.     

The role of imatinib plasma level testing in gastrointestinal stromal tumor

The management of patients with gastrointestinal stromal tumor (GIST) has markedly advanced over the past 10 years. Imatinib has exceptional activity in controlling gastrointestinal stromal tumor (GIST) due to inhibition of the constitutively active conformation of KIT and PDGFRA which is found in the majority of patients with GIST. Although some patients may experience prolonged disease control while on imatinib, most patients will develop imatinib resistance within 2-3 years on therapy. A recent retrospective analysis demonstrated a relationship between imatinib plasma levels and progression-free survival in patients with advanced GIST. Plasma imatinib levels in this study were unrelated to the daily administered dose of imatinib. A prospective trial is underway in order to evaluate whether modification of imatinib dose to achieve a target imatinib plasma level will impact patient outcome when compared to standard imatinib dosing in GIST ( http://www.clinicaltrials.gov , NCT01031628). This review will explore the current available data on the relationship between imatinib plasma levels, response to treatment, and other prognositic factors as well as discuss the implications of this data for possible future therapeutic approaches.     

Combination of vitamin K2 plus imatinib mesylate enhances induction of apoptosis in small cell lung cancer cell lines

Imatinib mesylate, an inhibitor of tyrosine kinases including BCR-ABL and KIT, inhibits the growth inhibition of small cell lung cancer (SCLC) cell lines in vitro. However, clinical trials of imatinib mesylate alone in patients with SCLC resulted in unsatisfactory outcomes. Vitamin K2 (menaquinone-4: VK2) induces apoptosis and differentiation in leukemia cells. We recently reported that VK2 also induces apoptosis in lung cancer cell lines. In the present study, we focused on the in vitro combined effects of imatinib mesylate plus VK2 on SCLC cell lines such as LU-139, LU-130, NCI-H69 and NCI-H128. Treatment with imatinib mesylate and VK2 for 96 h resulted in suppression of cell growth in a dose-dependent manner in all cell lines tested. The 50% inhibitory concentration (IC50) for imatinib mesylate ranged from 17-29 microM, whereas the IC50 for VK2 ranged from 16-64 microM. Combined treatment of imatinib mesylate plus VK2 resulted in pronounced inhibition of cell growth. The morphologic features of cells treated with imatinib mesylate and VK2 were typical of apoptosis. Since VK2 is a safe medicine without prominent adverse effects, treatment of patients with SCLC could derive therapeutic benefits from a combination of imatinib mesylate and VK2.     

伊马替尼治疗慢性粒细胞白血病患者在生育时中断药物治疗对胎儿和患者自身的影响

目的:分析伊马替尼治疗慢性粒细胞白血病（chronic myeloid leukemia,CML）患者在生育时中断药物治疗对胎儿和患者自身的影响。方法:回顾性分析本科室21例CML合并妊娠患者在接受伊马替尼治疗后的影响。结果:21名接受伊马替尼治疗的CML患者中有6名为意外怀孕,15名为计划怀孕。有生育意愿的女性患者需达到血液学或细胞学缓解至少两年,在受孕前1个月和孕期前3个月停服伊马替尼,男性患者则在生育前一个月停止接受伊马替尼的治疗。所有意外受孕的患者在孕期均未停止服用伊马替尼。21名患者共生产9名男婴和7名女婴（其中1名尿道下裂,1名轻度脑水肿）,其余有2名自然流产,3名选择性流产。结论:鼓励接受伊马替尼治疗的CML患者有计划的生育,对于治疗期间意外怀孕的患者,伊马替尼则会导致自然流产或先天性异常。     

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

Clinical studies using the tyrosine kinase inhibitor, imatinib mesylate (Gleevec?), in glioblastoma, have shown no major inhibition of tumor growth or extension of survival for patients, unlike those in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The molecular mechanisms of action of imatinib in glioblastoma cells are still not well understood. In this study, we investigated the effects of imatinib on the platelet derived growth factor receptor (PDGFR) downstream signaling pathways as well as on other cellular functions in human glioblastoma cells. NIH3T3 fibroblast and K562 CML cells were used for comparison. Western blot analysis demonstrated that imatinib was more effective in inhibiting the activated rather than the quiescent forms of the target proteins. Furthermore, the imatinib treatment induced the sustained activation of extracellular signal-regulated kinase (ERK 1/2) signaling as well as components of other downstream signaling pathways, such as PI3K/Akt, STAT3 and p38MAPK. Prior stimulation of the malignant cells with exogenous PDGF-BB partially abrogated this activation. Further analysis indicated that the activation of ERK induced by the imatinib treatment was related to the S-phase re-entry of the cell cycle in one of the three glioma cells. Imatinib significantly inhibited cell migration but not cell growth. The combination treatment of imatinib with a MEK or PI3K inhibitor resulted in significant growth inhibition but did not inhibit cell migration beyond the inhibition achieved with the imatinib treatment alone. The treatment of glioma cells with small interfering RNA inhibiting PDGFRB, however, evoked enhanced Akt signaling. These results indicate that the imatinib treatment of malignant glioma does not result in significant inhibitory effects and should be used with caution.     

Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate

BACKGROUND: The aim of the study was to analyze the surgical possibilities of unresectable and/or metastatic GIST CD117(+) patients during imatinib treatment. METHODS: We analyzed the results of surgery in 141 patients treated with imatinib for initially inoperable and/or metastatic GIST CD117(+). Median follow-up time was 12 months (range: 3-26). RESULTS: Surgery was performed as subsequent treatment in 24 patients (Group I, 17%) for resection of residual disease after complete/partial response and lack of further response to imatinib and as salvage therapy in eight patients (Group II, 6%), who progressed on initially successful imatinib therapy. In Group I, the viable GIST cells were not detected histologically in only three resection specimens. The first five patients in Group I did not receive imatinib further and we observed four recurrences. In next 19 patients, continuing imatinib after surgery, we observed only one relapse. In Group II, we continued imatinib therapy after high-risk surgical procedures, but in five patients we observed subsequent progression. CONCLUSIONS: Surgical removal of residual disease during imatinib treatment may allow for complete remission in selected GIST patients after response to therapy, theoretically prolonging durable remission, but it is necessary to continue imatinib for its maintenance.     

Possible role for gene expression profiling in predicting responses to conventional or targeted drugs in patients with chronic myeloid leukemia

The introduction of imatinib has profoundly changed the clinical management and prognosis of patients with chronic myeloid leukemia (CML). However, prognostic scores introduced during the interferon-era have lost their prognostic value when applied to patients treated with imatinib. Gene expression profiling represents a unique and powerful tool for the identification of responders and non-responders to cancer therapy. Thus, this technology may also represent a valuable strategy to identify patients with insufficient response prior to or during imatinib treatment, who might benefit from alternative treatment modalities. This review will briefly summarize the recently published data on gene expression profiling for imatinib response prediction in CML patients.     

Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007

Chronic myeloid leukemia cells contain a Bcr-Abl oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal cause of the leukemia. The use of the first-generation tyrosine kinase inhibitor imatinib to inhibit the dysregulated kinase activity has proved remarkably successful, and imatinib as a single-agent is now considered to be the best initial treatment for the majority of adult patients in chronic phase. For patients who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-activated, second generation tyrosine kinase inhibitors, such as dasatinib or nilotinib, might restore the kinase inhibition. Allogeneic stem cell transplantation is now generally offered to older patients in whom imatinib therapy, and perhaps dasatinib or nilotinib also, have failed; efforts to establish firm criteria for the selection of second-line therapies after imatinib failure continue. At this time, children and younger adults should probably be considered for transplantation as first-line treatment.     

Resistance to imatinib in chronic myelogenous leukemia: Mechanisms and clinical implications

The introduction of imatinib represented a breakthrough in the treatment of chronic myelogenous leukemia (CML). However, about 20% of patients treated in early chronic-phase CML are off therapy after 6 years because of resistance or intolerance, and most patients taking imatinib remain BCR-ABL-positive at the molecular level, indicating primary refractoriness of a leukemic subpopulation. Patients with advanced disease often do not respond, or they eventually relapse. Resistance frequently is associated with mutations in the kinase domain of BCR-ABL. Other mechanisms leading to reactivation of BCR-ABL or preventing sufficient BCR-ABL inhibition also exist. Resistance of patients with continued BCR-ABL inhibition despite leukemic progression indicates clonal evolution triggered by BCR-ABL-independent mechanisms. Current efforts to optimize BCR-ABL-targeted treatment focus on the difficulty in reaching CML stem cells. Success will most likely depend on integration of combined treatment algorithms—whether they be a combination of molecules interfering with signaling pathways or additional immune-based treatment adjuncts.     

Imatinib for hepatocellular cancer--focus on pharmacokinetic/pharmacodynamic modelling and liver function

The effects of imatinib are partly mediated by the inhibition of platelet-derived growth factor (PDGF), which is highly expressed in the liver. In this phase-I/II trial pharmacokinetic parameters of imatinib given for hepatocellular cancer were similiar to those previously derived from CML patients. The AUC of N-desmethyl-imatinib depended on liver function; the metabolism of imatinib was otherwise comparable to other populations. During short-termed imatinib treatment (4 weeks, 400 mg/d), plasma PDGF significantly decreased. The AUC of N-desmethyl-imatinib could best be attributed to the pharmacodynamic effect of PDGF inhibition (r = −0.679 [95% CI: −0.917 to −0.0868], p = 0.031).     

First-Line management of CML: a state of the art review

With the advent of imatinib, an inhibitor of the fusion Bcl-Abl tyrosine kinase that is responsible for the disease phenotype, first-line treatment of chronic myelogenous leukemia (CML) has undergone rapid changes. As a consequence of the success of imatinib, allogeneic stem cell transplantation (allo-SCT) has moved from the first-line indication to an option that is usually considered for patients without optimal response to imatinib or those for whom treatment with imatinib has failed. First-line use of interferon-alpha (IFN-alpha), with or without cytarabine or hydroxyurea, is now rarely considered. Most patients with newly diagnosed chronic-phase CML experience complete cytogenetic responses during imatinib treatment, but continued treatment is necessary to prevent cytogenetic or molecular relapse. Cumulative evidence with imatinib and IFN-alpha show that experiencing early and deep responses is important in preventing progression to more advanced phases of the disease. These features emphasize the need to carefully monitor patients for residual disease and provide guidance on treatment options in the event of imatinib intolerance or failure. This article reviews the current role of allo-SCT, imatinib, and IFN-alpha in treating newly diagnosed chronic-phase CML, highlighting the benefits and challenges of long-term patient management, and discusses emerging trends.     

Imatinib sensitizes CLL lymphocytes to chlorambucil.

The effect of imatinib on chlorambucil (CLB) cytotoxicity in chronic lymphocytic leukemia (CLL) lymphocytes was examined in vitro. Imatinib sensitizes the WSU and I83 human CLL cell lines, 10- and two-fold, respectively, to CLB. Furthermore, in primary cultures of malignant B-lymphocytes obtained from 12 patients with CLL (seven patients were untreated and five treated with CLB), imatinib synergistically sensitized these lymphocytes from two- to 20-fold to CLB. This synergistic effect was observed at concentrations of imatinib (相似文献   

Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for chronic myeloid leukemia (CML). The majority of patients continue treatment for their lifespan because discontinuation generally results in relapse. Many patients treated with imatinib experience adverse events (AEs) at some time during their treatment. Commonly encountered AEs and their management are well known. However, in addition to the common AEs with imatinib, there is a significant number of patients who display either uncommon or delayed AEs. These events can involve cardiac, renal, or dermatologic problems, and fluid retention. Herein, we review these less-than-common side effects and the hazard of administering imatinib during pregnancy. While chronic treatment with imatinib has revolutionized CML prognosis, physicians should be aware of both the common and uncommon adverse reactions.     

Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate

BACKGROUND:

The authors sought to determine the incidence and severity of cardiovascular toxicity caused by imatinib mesylate in gastrointestinal stromal tumor (GIST) and other sarcoma patients, and to explore cardiotoxicity caused by imatinib mesylate using cell culture and in vitro models.

METHODS:

To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving imatinib mesylate, the authors performed a retrospective analysis of 219 consecutive patients treated with imatinib mesylate. In vitro studies of imatinib mesylate on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with imatinib mesylate were performed to define the potential cardiotoxic effects of imatinib mesylate.

RESULTS:

Grade 3 or 4 potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of imatinib mesylate. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in <1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response.

CONCLUSIONS:

The authors concluded that imatinib is an uncommon cause of cardiotoxicity, and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our preclinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore, the cardiac consequences of long‐term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib‐treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure. Cancer 2010. © 2010 American Cancer Society.     

BCR-ABL mutations in chronic myeloid leukemia

The advent of imatinib has been a major breakthrough in chronic myeloid leukemia (CML) treatment. A few patients treated with imatinib are either refractory to imatinib or eventually relapse. Resistance is frequently associated with mutations in the kinase domain of BCR-ABL. Over 100 point mutations coding for single amino acid substitutions in the BCR-ABL kinase domain have been isolated from CML patients resistant to imatinib treatment. Most reported mutants are rare, whereas 7 mutated residues comprise two-thirds of all mutations detected. BCR-ABL mutations affect amino acids involved in imatinib binding or in regulatory regions of the BCR-ABL kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. The early detection of BCR-ABL mutants during therapy may aid in risk stratification as well as molecularly based treatment decisions.