Vincristine potentiates the anti-proliferative effect of an aurora kinase inhibitor, VE-465, in myeloid leukemia cells

Aurora kinases play an essential role in the regulation of mitosis. The kinases are overexpressed in a variety of cancer cells and are involved in tumorgenesis. Although aurora kinase inhibitors are potential agents for treatment of leukemia, the establishment of efficacious combination therapies is an attractive approach for making good use of these agents. In this study, we examined the effects of a specific aurora kinase inhibitor, VE-465, in combination with various conventional anti-leukemia agents, including doxorubicin, daunorubicin, idarubicin, mitoxantron, cytosine arabinoside, vincristine and etoposide, on acute myeloid leukemia cell lines (HL60, U937, THP-1 and KY821), chronic myeloid leukemia cell lines (KCL22, K562 and KU812) and primary leukemia cells. We found that a combination of VE-465 and vincristine had a synergistic/additive inhibitory effect on the growth of leukemia cells. VE-465 initially increased G2/M-phase cells, followed by induction of sub-G1 cells. Vincristine enhanced this effect of VE-465. The combination of VE-465 and vincristine increased the levels of cleaved caspase 3, cleaved caspase 7, cleaved caspase 9, cleaved PARP and Phospho-Chk2, suggesting that the combination caused Chk2-mediated activation of the G2/M checkpoint, resulting in sequential induction of apoptosis. Interestingly, the combination markedly decreased the level of Phospho-ERK1/2, suggesting that the combination alters a network of cellular signaling pathways. In contrast, combinations of VE-465 and other agents showed no synergistic inhibitory effect but rather had an antagonistic effect. In conclusion, our results indicate the utility of the combination of VE-465 and vincristine as a potential therapy for myeloid leukemia.     

Stathmin基因表达与肿瘤化疗药物敏感性的关系

目的:探讨8种肿瘤细胞对长春新碱(vincristine, VCR)和泰索帝(docetaxel, DOC)两种化疗药物的敏感性以及该敏感性与肿瘤细胞内Stathmin基因表达之间的关系. 方法:采用MTT法和形态学观察,根据两种药物对细胞的相对抑制率,分析8种肿瘤细胞对两种药物的敏感情况;应用实时荧光定量PCR技术分析比较上述细胞Stathmin基因表达情况. 结果: 8种肿瘤细胞对VCR的敏感程度(相对抑制率)依次为:骨肉瘤细胞9607,58%,9901, 56%;宫颈癌细胞Hela, 37%;肝癌细胞HHCC, 34%;肺癌细胞A549,31%;喉癌细胞Hep-2,17%;胃癌细胞MKN45, 16%;肝癌细胞7721,15%. 对DOC敏感程度依次为: 9607, 48%; Hela,46%;9901,44%;Hep-2, 34%;A549, 31%;MKN45,15%;HHCC, 12%;7721, 3%;Stathmin基因在各肿瘤细胞中具有不同程度的表达,其表达强度与各肿瘤细胞对两种药物的敏感性有关. 结论:肿瘤细胞中Statnmin基因表达水平与其化疗药物敏感程度有关,检测Statnmin基因表达水平对临床化疗药物的选择有一定的指导意义.     

Management of complicated hemangiomas with vincristine/vinblastine: Quantitative response to therapy using MRI

Purpose

To quantify the efficacy of vincristine and vinblastine in the treatment of complicated hemangiomas.

Design

Retrospective review.

Methods

Charts were reviewed to identify patients treated with vincristine or vinblastine for complicated hemangiomas from August 2002 to October 2007. Only patients who received both a pre and post-treatment magnetic resonance imaging (MRI) were considered. A database was created which includes patient gender, age at treatment initiation, rationale for treatment, hemangioma location, number of cycles of chemotherapy received, and complications of treatment. A single pediatric radiologist calculated lesion volumes from both pre and post-treatment MRI which were compared to quantify treatment response.

Results

Seven patients (2 male, 5 female) met criteria. Mean age at treatment initiation was 20 weeks (median 14, range 5-60). Rationale for treatment included four patients (57%) with proptosis/orbital compromise and one patient each (14%) with heart failure, airway compression, and hemangiomatosis with rapid growth of multiple lesions. Patients received a mean of 2.86 cycles of chemotherapy (median 3, range 1-5).Twelve lesions were identified and analyzed for pre and post-treatment volume on MRI in the seven patients. Eleven of twelve (92%) lesions decreased in size after treatment. The mean volume ratio of hemangiomas at the conclusion of chemotherapy was 0.45 compared to pre-treatment size (median 0.18, range 0-2.19) Orbital compromise, airway compression, and cardiac failure either improved or resolved in all patients.Three complications of treatment were seen in seven patients (42%) including bacteremia with anemia, peripheral neuropathy and motor delay. All complications resolved after cessation of chemotherapy.

Conclusions

Treatment of complicated hemangiomas with vincristine or vinblastine can control growth and improve symptoms in the majority of patients. Treatment often requires multiple cycles of chemotherapy. Complications of treatment are common, but reversible.     

Combined Therapy with Rituximab Plus Cyclophosphamide/Vincristine/Prednisone for Sjogren’s Syndrome-Associated B-Cell Non-Hodgkin’s Lymphoma

Sjogren’s syndrome (SS) is characterized by an increased risk of developing non-Hodgkin’s lymphoma (NHL). Optimal treatment for NHL-complicating SS is not clearly established. NHL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We report clinical and immunological data of a patient with SS and NHL who was treated with a regimen consisting of cyclophosphamide/vincristine/prednisone (CVP) plus rituximab. A 68-year-old women had a 26-year history of SS and autoimmune thyroiditis. The clinical course of SS was complicated with severe splenomegaly. An increased percentage of CD19+ B cells (up to 30%) was detected in peripheral blood during follow-up. Clonal rearrangement of immunoglobulin heavy chain was detected. Low-grade B marginal zone lymphoma was diagnosed (peripheral blood immunophenotype: CD19 + CD20 + CD23 + sIg + Kappa; bone marrow immunophenotype: 25% lymphocytes; CD19 + CD20 + CD79A/BCL2+). She received a total of six cycles of CVP plus rituximab (375 mg/m²). Therapy was well tolerated, and B lymphocytes were depleted from the peripheral blood. Splenomegaly normalized. No evidence of neoplastic infiltration was detected in bone marrow after completion of therapy, while certain symptoms of SS (sicca and arthralgia) improved with treatment. CVP plus rituximab proved effective in a patient with SS with NHL.     

蛋白激酶C的下调与KBV200细胞多药耐药性的关系

目的　探讨蛋白激酶C (PKC)在肿瘤多药耐药 (MDR)中的作用。方法　3 2 P掺入法测定PKC的活性 ;Westernblot法检测KBV2 0 0细胞株PKC亚型的表达和亚细胞分布 ;实验组用十字孢碱 (SP)预孵育KBV2 0 0细胞 ;MTT法检测耐药株KBV2 0 0细胞的耐药性。结果　SP可下调膜组分和浆组分的PKC活性及总活性 ;使PKCα膜组分和浆组分的表达均降低 ,PKCβ的膜组分消失 ,浆组分PKCβ的表达稍增强 ,PKCε的膜组分和浆组分表达无变化 ;SP可降低VCR、ADR对KBV2 0 0细胞的IC50 值 (P <0 0 1)。结论　SP使KBV2 0 0细胞耐药性降低 ,可能与下调PKC有关。     

阿霉素和长春新碱对pRb-胃癌细胞株的影响

目的：探索一种对Rb基因表达异常之胃癌细胞的化疗方案。方法：用Rb-CMV质粒转染Rb表达阴性的胃癌AGS细胞株，然后将25ng/ml阿霉素和100ng/ml长春新碱序贯加入两组细胞，应用MTT、流式细胞技术来测定转染前后此细胞株对序贯用药后的活性及细胞周期变化。结果：预先作用的阿霉素使Rb阳性胃癌AGS细胞阻滞于细胞周期的G1／S期，而不影响Rb阴性胃癌AGS细胞增殖。阿霉素和长春新碱序贯用药对Rb阴性胃癌AGS细胞有显著细胞毒性作用，而对Rb阳性胃癌AGS细胞的毒性作用轻微。结论：由于绝大多数正常组织的Rb是正常表达，而在胃癌中表达大多是阴性，故此联合用药有望用于Rb表达阴性胃癌的治疗。     

骨水泥掺入常用化疗药的释放及活性

目的 明确常用化疗药丝裂霉素、长春新碱和5-F尿嘧啶掺入骨水泥后的释放及活性。方法 采用洗提法和MTT法测量药物的释放及活性。结果 三种药物均可从骨水泥中释放并具有杀伤肿瘤细胞效应。结论 骨水泥携带抗癌药具有抗肿瘤效应。     

抗癌药1,2:5,6-二去水卫矛醇与长春新碱联合用药的实验研究

去水卫矛醇(DAG)与长春新碱(VCR)联合使用,对小鼠淋巴细胞白血病L_(1210)有协同疗效,疗效强度决定于给药方案和剂量。先给DAG,24 h后给VCR,协同疗效最高。DAG剂量是影响疗效的主要因素,最佳剂量为3.0 mg/kg。琼脂扩散合试验亦证明二药有方案依赖性协同作用。二药合用对小鼠骨髓干细胞仅有微弱的协同杀灭作用。