Hepatic protective effect of grape seed proanthocyanidin extract against Gleevec-induced apoptosis, liver Injury and Ki67 alterations in rats

ABSTRACT Gleevec (imatinib) is an antineoplastic chemotherapeutic agent used in the treatment of many types of cancer. The current study was conducted to examine the possible modifying effects of grape seeds proanthocyandins extract (GSPE) against apoptosis, liver injury and Ki67 alterations induced by Gleevec in male rats. 40 male albino rats were equally divided into four groups (First and second groups were control and GSPE groups; third group was Gleevec group and fourth group was treated with Gleevec and GSPE). Gleevec induced elevations in P53 and depletion of Bcl2 levels in liver tissues were compared with the control group. Liver sections in rats treated with Gleevec exhibited marked cellular infiltrations, vacuolar degeneration hepatocytes, numerous apoptotic cells, and congestion in central and portal veins, as well as a significant increase in the proliferating of Ki67 after Gleevec injection as compared with control group. In contrast, treatment with Gleevec and GSPE showed a moderate to good degree of improvement in hepatocytes with a significant increase in Ki67, a decrease in P53 and an increase in Bcl2 levels in liver tissues compared to treatment with Gleevec. Therefore, Gleevec induces apoptosis, injury and Ki67 changes in rat liver, whereas GSPE modulates these alternations.

Imatinib-induced Psoriasiform Drug Eruption in a Patient with a Gastrointestinal Stromal Tumor / 대한피부과학회지

Imatinib mesylate (Gleevec(R)) is a small-molecule inhibitor that selectively inhibits the tyrosine kinase family, including mutated KIT oncoproteins in gastrointestinal stromal tumors (GIST). However, cutaneous reactions to imatinib are common and occur in 7.0% to 88.9% of patients. Nonspecific skin rashes, facial edema, and pruritus are the most common adverse reactions. However, development of psoriasiform drug eruption owing to the drug has rarely been reported. Herein we report on a 66-year-old male patient with GIST who had taken imatinib (400 mg/day) for 2 months. He developed erythematous scaly macules and papules on the trunk and extremities. Histopathological findings were compatible with a psoriasiform drug eruption.

A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia

p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.

Influence of Gleevec on expression of miR-146a,miR-29b and DNMT in K562 cells / 重庆医学

Objective To investigate the changes of microRNA (miR)-146a ,miR-29b expression levels and the 3 kinds of meth-ylase DNMT1 ,DNMT3a and DNMT3b levels in K562 cell lines after BCR/ABL inhibitor Gleevec treatment .Methods The half maximal inhibitory concentration(IC50 ) of Gleevec on K562 cells was detected by the MTT method .The stem loop primers method and the fluorogenic quantitative PCR were adopted to detect miRNAs and the methylase gene level .Results IC50 of Gleevec acting on K562 cells was 40 .85μmol/L .After Gleevec action ,miR-29b showed the increasing trend ,but 3 kinds of methylase expression level were decreased to some extent .Gleevec could significantly increase the miR-146a level in K562 cells(P<0 .05) .Conclusion Gleevec can influence the expression of miR-146a ,miR-29b and DNMTs levels in K562 cells .

Imatinib Mesylate (Gleevec(TM))-induced Lichenoid Drug Eruption Improved by Tentative Dose-reduction and Topical Steroid / 대한피부과학회지

Imatinib mesylate (Gleevec(TM)) is an oral anticancer drug. It works as a selective and competitive inhibitor of tyrosine kinases such as bcr-abl protein, c-kit, and platelet-derived growth factor receptors (PDGFR). Gleevec(TM) is a first-line therapeutic agent for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors, but causes various adverse cutaneous reactions. We herein report on a case of lichenoid drug eruption induced by Gleevec(TM) in a patient with a malignant gastrointestinal stromal tumor.

The Sensitivity of Gene Mutant Related to Gastrointestinal Stromal Tumor to Gleevec / 中国肿瘤临床

Objective: To explore the sensitivity of Kit or PDGFRA mutants related to gastrointestinal stromal tumor (GIST) to Gleevec.Methods: The recombinant plasmids of KIT Del559-560, KIT Ins IPYD579, PDGFRA D842V and PDG-FRA L839P gene mutants were transiently transformed into the CHO cells by liposome methods.Western blot was used to detect the expression of the related protein and their phosphorylated forms after the cells were incubated with Gleevec for 90 min.At 72 hours after incubation with Gleevec, MTT was used to detect cell proliferation.Results: Western blot results showed that Gleevec at 0.1 μM can notably reduce phosphorylation of KIT Del559-560.Gleevec at 1μM completely blocked phosphorylation of KIT Ins IPYD579 and PDGFRA L839P, but did not affect PDGFRA D842V phosphorylation.MTT analy-sis indicated that growth of CHOPDGFRA L839P was inhibited by Gleevec at 1μM, however, CHOPDGFRA D842V was re-sistant to Gleevec at 5 μM.Conclusion: Gleevec can decrease the expression of phosphorylated protein CHOPDGFRA L839P and CHOKIT Ins IPYD579, and can remarkably inhibit the proliferation of cells containing PDGFRA L839P mutant.

Morphological Features of Metastatic Gastrointestinal Stromal Tumors after Gleevec Treatment: Two Cases Report

We report two patients with metastatic gastrointestinal stromal tumors (GISTs) with a focus on the morphological features related to Gleevec treatment. In case 1, a 50-year-old woman presented with a 1.8 cm metastatic GIST in the liver after resection of a gastric GIST. Majority of the metastatic tumor showed fibrosis and hyalinization after 8 weeks of Gleevec treatment. CD117-positive cells were present in approximately 1% of the overall tumor. In case 2, a 2 cm and 14 cm metastatic liver masses were found in a 54-year-old man who had a rectal GIST. After 4 weeks of Gleevec treatment, metastatic tumors showed a decrease in size on CT scan. The metastatic tumors showed a decrease in number of tumor cells. The hemorrhage, cystic changes, necrosis, and fibrosis made up approximately 90% of the tumor. The morphological features related to Gleevec treatment are important for correct diagnosis and evaluation of tumor response and prognosis.

Clinical features and therapy of chronic myelogenous leukemia in childhood / 解放军医学杂志

Objective To investigate the clinical features of the childhood chronic myelogenous leukemia (CCML), including the pathogenesis, incidence, clinical characteristics, diagnostic criterion, prognostic significance and the treatment strategies, etc. Method The data of 148 cases of CCML were comprehensively reviewed and analyzed, and international and domestic literature in the last two decades was reviewed. Results The CCML was found to be rare with unknown etiology, and was an acquired malignant disease of clonal proliferation of hematopoietic stem cells in children. The disease included two clinical types: adult CCML and juvenile CCML. 72.3% of CCML patients were diagnosed as the adult CCML. The clinical feature of CCML consisted of fatigue, low fever, anemia, hepatomegaly, splenomegaly, and lymphadenopathy. The laboratory findings of a typical CCML patient comprised of peripheral blood leukocytosis, basophilia and eosinophilia, myeloid differentiation in different stages, and increased megakaryocytes. The immunohistochemical features of the CCML consisted of highly positive MPO and CD68, significant lowering of neutrophil alkaline phosphatase (NAP), positive for Philadelphia chromosome (Ph) or chimeric BCR/ABL gene, etc. But in most cases of juvenile CCML, the Philadelphia chromosome could not be detected. The Gleevec therapy and hematopoietic stem cell transplantation (HSCT) might give better treatment result for CCML than the traditional therapy. Conclusions CCML has its characteristic clinical feature. The key of good therapeutic result is early diagnosis and treatment. The optimal therapy for CCML is Gleevec regime and HSCT.

Morphological evaluation of bone marrow during initial stage of Gleevec therapy for treatment of chronic myelogenous leukemia / 解放军医学杂志

Objective To morphologically evaluate the bone marrow (BM) smear specimens collected from the patients with chronic myelogenous leukaemia (CML) in accelerated phase and blastic phase receiving a short term Gleevec therapy, and to determine its clinical significance in evaluating the changes in disease condition to guide the treatment. Methods Sequential BM smear specimens of 16 Ph positive CML patients, including 9 in accelerated-phase and 7 in blastic-phase, were examined before and 3,6 and 9 weeks after Gleevec treatment (0.4/d or 0.6g/d, PO) with routine method. Periodic acid-Schiff reagent (PAS) staining was performed for a proper identification of abnormal erythroid precursor cells. Results The treatment rapidly caused following conspicuous BM changes in the process: both cellular proliferation and neutrophil granulopoiesis decreased significantly, while the accumulation of erythroid precursor cells increased obviously, and megakaryocytes decreased markedly at 3rd week. A few patients showed no such changes, but an accumulations of erythroid precursor cells, leading to misdiagnosis in some one third of the patients. In 21 percent of patients, in whom no erythroid cells were found, were classified into accelerated phase and blast phase based on both WHO classification system and FAB system. In fact the increase in red system was a bone marrow response to anemia caused by Gleevec therapy. If a condition of severe cellular proliferation of BM with a lower WBC and platelets appeared, most patients could not tolerate the therapy, then it should be ceased. Conclusion Initial treatment with Gleevec therapy exerts pronounced changes in BM morphology, which can be used as a simple and effective method to evaluate the outcome of the patients.