Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have performed a Phase I clinical trial with the naturally occurring flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone). Quercetin has antiproliferative activity in vitro and is known to inhibit signal transduction targets including tyrosine kinases, protein kinase C, and phosphatidyl inositol-3 kinase. Quercetin was administered by short i.v. infusion at escalating doses initially at 3-week intervals. The first dose level was 60 mg/m2; at the 10th dose level of 1700 mg/m2, dose-limiting nephrotoxicity was encountered, but no myelosuppression. At the preceding dose level of 1400 mg/m2, five patients were treated at 3-week intervals, and another eight patients were treated on a once-weekly schedule; overall, 2 of 10 evaluable patients had renal toxicity, 1 at grade 2 and 1 at grade 4. We therefore treated other patients at 945 mg/m2 (eight at 3-week intervals and six at weekly intervals); 3 of 14 patients had clinically significant renal toxicity, 2 patients with grade 2 and 1 patient with grade 3. Patients treated on the weekly schedule did not have cumulative renal impairment but did have a fall in the glomerular filtration rate of 19 +/- 8% in the 24 h after drug administration. We recommend 1400 mg/m2 as the bolus dose, which may be given either in 3-week or weekly intervals, for Phase II trials. Quercetin pharmacokinetics were described by a first-order two-compartment model with a median t(1/2)alpha of 6 min and median t(1/2)beta of 43 min. The median estimated clearance was 0.28 liter/min/m2, and median volume of distribution at steady state was 3.7 liter/m2. In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited following administration of quercetin at 1 h, which persisted to 16 h. In one patient with ovarian cancer refractory to cisplatin, following two courses of quercetin (420 mg/m2), the CA 125 had fallen from 295 to 55 units/ml, and in another patient with hepatoma, the serum alpha-fetoprotein fell. In conclusion, quercetin can be safely administered by i.v. bolus at a dose injection. The plasma levels achieved inhibited lymphocyte tyrosine kinase activity, and evidence of antitumor activity was seen.
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PMID:Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. 981 16

Hepatic and peritoneal metastases are the most frequent metastatic lesions in patients with gastrointestinal stromal tumors (GIST), and may result in intra- or extrahepatic cholestasis and altered drug metabolism. While the tyrosine kinase inhibitor imatinib, which has been recently shown to represent the treatment of choice for GIST, is primarily metabolized by the liver, data on the pharmacokinetics and the tolerability of imatinib in patients with increased cholestasis parameters are not yet available. We here report on two patients who received imatinib in the presence of increased bilirubin and/or cholestasis parameters. With a follow-up duration of 3-4 months, we observed no toxicities outside of well-known side effects including some degree of myelosuppression and fluid retention. This report may aid in the decision of imatinib being given under close surveillance to this kind of patients.
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PMID:Imatinib mesylate therapy in patients with gastrointestinal stromal tumors and impaired liver function. 1239 70

The introduction of imatinib, a specific inhibitor of the Bcr-Abl tyrosine kinase, has dramatically changed the management of chronic myeloid leukemia (CML). More than 10,000 patients worldwide have been treated with imatinib in clinical trials, and a large body of information has accumulated about the use of this drug. The purpose of this article is to review practical guidelines in regard to optimal dosing, monitoring, managing common side effects such as myelosuppression, and potential drug interactions. The treatment recommendations are intended to optimize therapy with imatinib while taking into account a patient's specific circumstances.
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PMID:Practical management of patients with chronic myeloid leukemia receiving imatinib. 1461 62

Imatinib is a selective tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. An important clinical observation is that imatinib can affect the function of normal nonmalignant cells resulting in myelosuppression in treated patients. This observation is supported by the recent findings suggesting that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, the induction of a specific T cell response seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib in contrast to patients receiving interferon-alpha. Recent studies demonstrate that in vitro exposure of mobilized human CD34(+) progenitors to imatinib inhibits their differentiation into dendritic cells. This is of importance as some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T cell responses. Studies investigating the effects of imatinib on normal hematopoiesis are of interest because they might help us better understand the side effects observed clinically and might lead to the identification of novel therapeutic applications of the drug (e.g., in Bcr-Abl(-) myeloproliferative disorders and potentially as an immunomodulatory agent).
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PMID:Effect of tyrosine kinase inhibition using imatinib on normal lymphohematopoietic cells. 1595 10

The selective tyrosine kinase inhibitor imatinib (Glivec; Novartis International, Basel, Switzerland, http://www.glivec.com/content/home.jsp) is increasingly used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. In principle, the drug is well tolerated and clinical side effects are mostly moderate. However, it was shown that imatinib can affect the function of normal, nonmalignant cells, resulting in myelosuppression in treated patients. Recently, it has been demonstrated that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, in several in vitro studies and animal models, it was demonstrated that imatinib can affect the function and differentiation of antigen-presenting cells and inhibit the effector functions of T lymphocytes. Moreover, the induction of specific cytotoxic T cells seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib compared with patients receiving interferon-alpha. This is of importance because some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T-cell responses. Further studies investigating the effects of imatinib on normal hematopoiesis are of interest as they might lead to a better understanding of the clinically observed side effects and also might help identify new therapeutic applications of the drug, possibly in Bcr-Abl-negative myeloproliferative disorders and potentially as an immunomodulatory agent.
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PMID:Effects of imatinib on normal hematopoiesis and immune activation. 1614 Aug 70

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.
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PMID:[Hematological side effects of tyrosine kinase inhibition using imatinib]. 1642 5

In advanced cases of non-small cell lung cancer, cytostatic treatment has small but assessable effect on patient survival as opposed to only symptomatic therapy. Cytostatic drugs, however, are known to have numerous side effects including neurotoxicity, nephrotoxicity, and myelosuppression. Better knowledge of tumor biology has led to the discovery of several key molecular pathways. Due to their beneficial effect and side effect profile, epidermal growth factor receptor tyrosine kinase inhibitors (gefitinib, erlotinib) have now been included in clinical practice in the treatment of non-small cell lung cancer. The predictive characteristics for the indication of these drugs have not yet been cleared up and require further clinical studies. Under the Expanded Access Program it has become possible to give patients with advanced non-small cell lung cancer (stages III/B and IV) epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. Authors present here two cases to illustrate the beneficial effect of the drug when used as second or third line therapy. A more detailed study of the histological specimen (epidermal growth factor receptor expression as well as epidermal growth factor receptor gene mutation) will provide further information as to the anticipated efficacy for erlotinib.
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PMID:[Erlotinib in second/third line treatment for non-small cell lung cancer (NSCLC)]. 1767 81

SUNITINIB (SUTENT: Pfizer, New York, NY, U.S.A.) is an oral multi-targeted tyrosine kinase inhibitor approved for use in various solid tumour malignancies. Many side effects secondary to sunitinib have been documented. In particular, sunitinib administration is known to result in thrombocytopenia, with the cause being attributed to myelosuppression. Here, we present the first case report to demonstrate immune-mediated thrombocytopenia secondary to sunitinib administration.
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PMID:Drug-induced immune thrombocytopenic purpura secondary to sunitinib. 1859 89

Gemtuzumab ozogamicin (GO, Mylotarg) is a targeted therapeutic agent in which an anti-CD33 antibody is chemically coupled to a highly cytotoxic calicheamicin derivative through a hydrolysable linker. GO has improved the treatment outcome for a subgroup of acute myeloid leukemia (AML) patients, but its use is associated with severe myelosuppression and hepatotoxicity. Here, we report on a novel anti-leukemia agent, designated scFvCD33:sTRAIL, in which an anti-CD33 single chain fragment of variable regions (scFv) antibody fragment is genetically linked to soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). Normal CD33-positive monocytes were fully resistant to prolonged treatment with scFvCD33:sTRAIL, whereas treatment with GO resulted in substantial cytotoxicity. The activity of scFvCD33:sTRAIL towards AML cells was up to 30-fold higher than GO. The CD33-restricted anti-leukemia activity of scFvCD33:sTRAIL remained stable during prolonged storage at 37 degrees C, whereas GO showed a rapid increase in CD33-independent cytotoxicity. Moreover, scFvCD33:sTRAIL showed potent anti-leukemia activity towards CD33+ CML cells when treatment was combined with the Bcr-Abl tyrosine kinase inhibitor, Gleevec. Importantly, ex vivo treatment of patient-derived CD33+ AML tumor cells with scFvCD33:sTRAIL resulted in potent apoptosis induction that was enhanced by valproic acid, mitoxantrone and 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG). Taken together, scFvCD33:sTRAIL is superior to GO in terms of tumor selectivity, activity and stability, warranting its further development for the treatment of CD33-positive leukemias.
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PMID:A novel AML-selective TRAIL fusion protein that is superior to Gemtuzumab Ozogamicin in terms of in vitro selectivity, activity and stability. 1926 96

The discovery of an activating tyrosine kinase mutation JAK2V617F in myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has resulted in the development of JAK2 inhibitors, of which several are being evaluated in phase I/II clinical studies. It is important to recognize that because the V617F mutation is localized in a region outside the adenosine triphosphate (ATP)-binding pocket of JAK2 enzyme, ATP-competitive inhibitors of JAK2 kinase (like the current JAK2 inhibitors in the clinic) are not likely to discriminate between wild-type and mutant JAK2 enzymes. Therefore, JAK2 inhibitors, by virtue of their near equipotent activity against wild-type JAK2 that is important for normal hematopoiesis, may have adverse myelosuppression as an expected side effect, if administered at doses that aim to completely inhibit the mutant JAK2 enzyme. While they may prove to be effective in controlling hyperproliferation of hematopoietic cells in PV and ET, they may not be able to eliminate mutant clones. On the other hand, JAK inhibitors may have great therapeutic benefit by controlling the disease for patients with MPNs who suffer from debilitating signs (eg, splenomegaly) or constitutional symptoms (which presumably result from high levels of circulating cytokines that signal through JAK enzymes). Indeed, the primary clinical benefits observed so far in MF patients have been significant reduction is splenomegaly, elimination of debilitating disease-related symptoms, and weight gain. Most importantly, patients with and without the JAK2V617F mutation appear to benefit to the same extent. In this review we summarize current clinical experience with JAK2 inhibitors in MPNs.
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PMID:Therapeutic potential of JAK2 inhibitors. 2000 49


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