Application of pharmacodynamic assays in a phase Ia trial of Apo2L/TRAIL in patients with advanced tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3535-3535 ◽  
Author(s):  
Y. Pan ◽  
R. Xu ◽  
M. Peach ◽  
C. Huang ◽  
D. Branstetter ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Complete Analysis ◽  
Serum Samples ◽  
Signaling Complex ◽  
Apoptotic Markers ◽  
Effector Caspase ◽  
Luminescent Signal ◽  
Caspase Substrate ◽  
Dose Dependent ◽  
Advanced Tumors

3535 Background: Recombinant human (rh) Apo2L/TRAIL is a dual pro-poptotic receptor agonist (PARA) that induces apoptosis by binding to pro-apoptotic receptors DR4 and DR5, which recruit a death inducing signaling complex upon ligand binding. This results in activation of the effector caspase 3/7, that subsequently cleaves intracellular substrates to execute cellular apoptosis. A Phase1a trial is underway to evaluate the safety and tolerability of rhApo2L/TRAIL in patients with advanced tumors. The aim of this study was to develop and validate high-throughput pharmacodynamic assays to monitor rhApo2L/TRAIL activity in easily accessible patient samples such as serum. Methods: To monitor rhApo2L/TRAIL activity in patients, we optimized assays to measure the release of the apoptotic markers caspase 3/7, cytokeratin 18 (CK18), and genomic DNA (gDNA) in serum. Serum caspase 3/7 levels were monitored using the Caspase Glo kit, which generates a luminescent signal upon cleavage of a caspase 3/7 substrate; cleavage of the caspase substrate CK18 was measured using an optimized form of the M30 ELISA assay; gDNA was measured using a β-actin-specific TaqMan real-time PCR assay. Mice bearing Colo205 xenografts were treated with rhApo2L/TRAIL and sera were collected and assayed for apoptotic markers. Upon validating these assays, we monitored the levels of apoptotic markers in cancer patients who received rhApo2L/TRAIL. Results: We detected transient increases in apoptotic markers in mouse sera 8–24 hr after treatment with rhApo2L/TRAIL. This increase was dose-dependent and correlated with active caspase 3 detected by IHC in Colo205 tumors. In the phase Ia study, increases in serum caspase 3/7 and gDNA levels were observed in >50% of colorectal, lung and sarcoma patients evaluated. Preliminary analyses show the percentage of increase correlates using both analytes and is dose-dependent. Conclusions: These findings support the use of serum-based pharmacodynamic assays as a means to monitor rhApo2L/TRAIL activity in patients with advanced tumors. A complete analysis of all patient serum samples from the ongoing phase Ia trial will be reported. No significant financial relationships to disclose.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

Survivin expression in correlation with apoptotic activity in canine lymphomas

2017 ◽  
Vol 20 (2) ◽  
pp. 329-338 ◽  
Author(s):  
J. Sokołowska ◽  
K. Urbańska
Keyword(s):  
Cell Cycle ◽  
Caspase 3 ◽  
Survivin Expression ◽  
Human Tumor ◽  
Apoptotic Index ◽  
Dual Function ◽  
Mean Values ◽  
Apoptotic Markers ◽  
Apoptotic Activity ◽  
Hodgkin's Lymphomas

AbstractSurvivin regulates cell cycle and mitosis and has antiapoptotic properties. Because of its dual function survivin has been the subject of much research focusing on its role in tumorigenesis and the relationship between survivin expression and apoptotic and/or proliferative activity in many types of human tumor including non-Hodgkin’s Lymphomas. Such studies have not been conducted in canine lymphomas. The aim of this study was to evaluate the expression of survivin in canine lymphomas of low (5/25) and high (20/25) grades in relation to apoptotic markers (apoptotic index and index of caspase-3). Survivin was found in all examined lymphomas. Most tumors (18/25) showed survivin expression in 10%-25% of positive cells. Only in single cases was lower (0-10% positive cells, 1/25) or higher (25%-50% and >50% positive cells, 5/25 and 1/25, respectively) survivin expression. No significant differences between mean values of either index of survivin or apoptotic index was found between low and high grade lymphomas. However, such a difference among lymphoma grades was shown regarding the caspase-3 index. No correlation between the survivin index and either the apoptotic index or caspase-3 index was found, irrespective of the method of quantification: in whole specimens or in areas of low and high survivin expression. Positive correlation was consistently noted only between both apoptotic markers. The results indicate that survivin is commonly expressed in canine lymphomas. It seems that survivin does not exhibit anti-apoptotic activity in canine lymphomas. Lack of correlation between survivin expression and apoptotic markers could indicate its potential role in cell cycle activation in lymphoma cells.

scholarly journals Thrombospondin-1 Inhibits Angiogenesis and Promotes Follicular Atresia in a Novel in Vitro Angiogenesis Assay

Endocrinology ◽  
2010 ◽  
Vol 151 (3) ◽  
pp. 1280-1289 ◽  
Author(s):  
Samantha A. Garside ◽  
Christopher R. Harlow ◽  
Stephen G. Hillier ◽  
Hamish M. Fraser ◽  
Fiona H. Thomas
Keyword(s):  
Granulosa Cells ◽  
Caspase 3 ◽  
Polycystic Ovary ◽  
Dependent Manner ◽  
Ovary Syndrome ◽  
Angiogenesis Assay ◽  
Thrombospondin 1 ◽  
In Vitro Angiogenesis ◽  
Dose Dependent

Thrombospondin-1 (TSP-1) is a putative antiangiogenic factor, but its role in regulating physiological angiogenesis is unclear. We have developed a novel in vitro angiogenesis assay to study the effect of TSP-1 on follicular angiogenesis and development. Intact preantral/early antral follicles dissected from 21-d-old rat ovaries were cultured for 6 d in the presence or absence of TSP-1. At the end of the culture period, angiogenic sprouting from the follicles was quantified using image analysis. Follicles were fixed and sectioned, and follicular apoptosis was assessed by immunohistochemistry for activated caspase-3 in granulosa cells. The results showed that TSP-1 inhibited follicular angiogenesis (P < 0.01) and promoted follicular apoptosis (P < 0.001) in a dose-dependent manner. To determine whether the proapoptotic activity of TSP-1 is mediated by direct effects on granulosa cells, isolated granulosa cells were cultured with TSP-1 (0, 10, 100, and 1000 ng/ml) for 48 h. Apoptosis was quantified using a luminescent caspase-3/7 assay. TSP-1 promoted apoptosis of granulosa cells in a dose-dependent manner (P < 0.05), suggesting that TSP-1 can act independently of the angiogenesis pathway to promote follicular apoptosis. These results show that TSP-1 can both inhibit follicular angiogenesis and directly induce apoptosis of granulosa cells. As such, it may have potential as a therapeutic for abnormal ovarian angiogenesis and could facilitate the destruction of abnormal follicles observed in polycystic ovary syndrome.

scholarly journals Quercetin Alleviates the Immunotoxic Impact Mediated by Oxidative Stress and Inflammation Induced by Doxorubicin Expo-Sure in Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1906
Author(s):  
Mayada R. Farag ◽  
Attia A. A. Moselhy ◽  
Amany El-Mleeh ◽  
Samira H. Aljuaydi ◽  
Tamer Ahmed Ismail ◽  
...  
Keyword(s):  
Antioxidant Status ◽  
Fruits And Vegetables ◽  
Caspase 3 ◽  
Chemotherapeutic Agent ◽  
Morphological Changes ◽  
Apoptotic Markers ◽  
Tnf Α ◽  
Chemotherapy Patients ◽  
The Impact ◽  
Cat Gene

Doxorubicin (DOX) is a chemotherapeutic agent against hematogenous and solid tumors with undesirable side effects including immunosuppression. Quercetin (QUR), a natural flavonoid abundant in fruits and vegetables, has a potent antioxidant activity. The aim of the current study was to assess the impact of QUR on DOX-induced hematological and immunological dysfunctions in a rodent model. Randomly grouped rats were treated as follows: control, QUR alone (50 mg/kg for 15 days per os), DOX alone (2.5 mg/kg I/P, three times a week, for two weeks), and co-treated rats with QUR for 15 days prior to and concomitantly with DOX (for two weeks), at the doses intended for groups two and three. DOX alone significantly disrupted the erythrogram and leukogram variables. Serum immunoglobulin (IgG, IgM, and IgE) levels and the activities of catalase (CAT) and superoxide dismutase (SOD) and in spleen were declined. The DNA damage traits in spleen were elevated with an upregulation of the expression of the apoptotic markers (p53 and Caspase-3 genes) and the proinflammatory cytokines (IL-6 and TNF-α genes), while the expression of CAT gene was downregulated. These biochemical changes were accompanied by morphological changes in the spleen of DOX-treated rats. Co-treatment with QUR abated most of the DOX-mediated alterations in hematological variables, serum immunoglobulins, and spleen antioxidant status, pro-inflammatory and apoptotic responses, and histopathological alterations. In essence, these data suggest that QUR alleviated DOX-induced toxicities on the bone marrow, spleen, and antibody-producing cells. Supplementation of chemotherapy patients with QUR could circumvent the DOX-induced inflammation and immunotoxicity, and thus prevent chemotherapy failure.

scholarly journals Comparative Study on Pulmonary Toxicity in Mice Induced by Exposure to Unflavoured and Apple- and Strawberry-Flavoured Tobacco Waterpipe Smoke

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Abderrahim Nemmar ◽  
Suhail Al-Salam ◽  
Sumaya Beegam ◽  
Priya Yuvaraju ◽  
Badreldin H. Ali
Keyword(s):  
Pulmonary Toxicity ◽  
Nuclear Factor Kappa B ◽  
Caspase 3 ◽  
Inflammatory Cells ◽  
Airway Hyperreactivity ◽  
Histological Evaluation ◽  
Air Exposure ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Necrosis Factor

The use of flavoured tobacco products in waterpipe smoking (WPS) has increased its attractiveness and consumption. Nonetheless, the influence of flavourings on pulmonary toxicity caused by WPS remains unclear. Here, the pulmonary toxicity induced by plain (P)-WPS, apple-flavoured (AF)-WPS, and strawberry-flavoured (SF)-WPS (30 minutes/day, 5 days/week for 1 month) was investigated in mice. Control mice were exposed to air. Exposure to P-WPS or AF-WPS or SF-WPS induced a dose-dependent increase of airway hyperreactivity to methacholine. The histological evaluation of the lungs in all the WPS groups revealed the presence focal areas of dilated alveolar spaces and foci of widening of interalveolar spaces with inflammatory cells. In the lung, the activity of neutrophil elastase and myeloperoxidase and the concentrations of tumor necrosis factor-α and glutathione were increased by the exposure to P-WPS, AF-WPS, or SF-WPS. However, the levels of interleukin-6 and catalase were only increased in the AF-WPS and SF-WPS groups, while nitric oxide activity was only increased in the SF-WPS group. DNA injury was increased in all the WPS groups, but the concentration of cleaved caspase-3 was only elevated in the SF-WPS group. The exposure to either P-WPS or AF-WPS or SF-WPS increased the expression of nuclear factor kappa-B (NF-κB) in the lung. In conclusion, the exposure to P-WPS or AF-WPS or SF-WPS induces alterations in lung function and morphology and causes oxidative stress and inflammation via mechanisms that include activation of NF-κB. Overall, the toxicity of flavoured tobacco WPS, in particular SF-WPS, was found to be greater than that of unflavoured WPS.

scholarly journals Abrus agglutinin targets cancer stem-like cells by eliminating self-renewal capacity accompanied with apoptosis in oral squamous cell carcinoma

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770163 ◽  
Author(s):  
Niharika Sinha ◽  
Prashanta Kumar Panda ◽  
Prajna Paramita Naik ◽  
Tapas K Maiti ◽  
Sujit K Bhutia
Keyword(s):  
Reactive Oxygen Species ◽  
Oral Cancer ◽  
Caspase 3 ◽  
Glycogen Synthase ◽  
Reactive Oxygen ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Self Renewal ◽  
Fadu Cells ◽  
Dose Dependent

The accumulating evidences show that Abrus agglutinin, a plant lectin, displays a broad range of anticancer activity including cancer-specific induction of apoptosis; however, the underlying molecular mechanism of Abrus agglutinin–induced oral cancer stem cell elimination remains elusive. Our data documented that Abrus agglutinin effectively downregulated the CD44+ expression with the increased CD44− population in different oral cancer cells. After 24-h Abrus agglutinin treatment, FaDu cells were quantified for orosphere formation in ultra-low attachment plates and data showed that Abrus agglutinin inhibited the number and size of orosphere in a dose-dependent manner in FaDu cells. Furthermore, Abrus agglutinin hindered the plasticity of FaDu orospheres as supported by reduced sphere formation and downregulated the self-renewal property via inhibition of Wnt-β-catenin signaling pathway. Introduction of LiCl, a glycogen synthase kinase 3β inhibitor, rescued the Abrus agglutinin–stimulated inhibition of β-catenin and phosphorylated glycogen synthase kinase 3β in FaDu cell–derived orospheres confirming importance of Wnt signaling in Abrus agglutinin–mediated inhibition of stemness. In this connection, our data showed that Abrus agglutinin restrained proliferation and induced apoptosis in FaDu-derived cancer stem cells in dose-dependent manner. Moreover, western blot data demonstrated that Abrus agglutinin increased the Bax/Bcl-2 ratio with activation of poly(adenosine diphosphate–ribose) polymerase and caspase-3 favoring apoptosis induction in orospheres. Abrus agglutinin induced reactive oxygen species accumulation in orospheres and pretreatment of N-acetyl cysteine, and a reactive oxygen species scavenger inhibited Abrus agglutinin–mediated caspase-3 activity and β-catenin expression indicating reactive oxygen species as a principal regulator of Wnt signaling and apoptosis. In conclusion, Abrus agglutinin has a potential role as an integrative therapeutic approach for combating oral cancer through targeting self-renewability of orospheres via reactive oxygen species–mediated apoptosis.

Study on the antitumor activity and mechanism of novel targeted nanodrugs based on miRNA in cervical cancer

2020 ◽  
Vol 10 (8) ◽  
pp. 1218-1223
Author(s):  
Xinping Chen ◽  
Zhichao Ma ◽  
Juan Zhu ◽  
Weihua Xu ◽  
Junjie Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
Antitumor Activity ◽  
A549 Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
A549 Cells ◽  
Dependent Manner ◽  
Double Staining ◽  
Dose Dependent

The aim of this study was to investigate the effect of different concentrations of novel targeted nanodrugs based on miRNA on the antitumor activity and mechanism in cervical carcinoma A549 cells. The MTT method was used to determine the effect of different concentrations of novel targeted nanodrugs based on miRNA on A549 cell proliferation, and annexin V FITC/PI double staining flow cytometry was performed to analyze the effect of these nanodrugs on A549 cell apoptosis. Western blotting was performed to observe the effect of these nanodrugs on the expression of Bax, Bcl-2, and caspase-3-related genes involved in A549 cell apoptosis. Compared with the control group, the novel targeted nanodrugs based on miRNA significantly inhibited the proliferation of A549 cells in a time- and dose-dependent manner. Results of double staining flow cytometry demonstrated that these nanodrugs could increase the apoptotic rate of A549 cells in a dose-dependent manner 48 h later. Western blotting revealed that these nanodrugs could upregulate the expression of Bax and caspase3 genes and downregulate the expression of Bcl-2 gene. Nanodrugs display an obvious antitumor activity in vitro, and the underlying mechanism may be associated with the upregulation of Bax and caspase-3 gene expression and the downregulation of Bcl-2 gene expression.

JS-K, a Novel Nitric Oxide (NO) Generator, Induces Cytochrome c Release and Caspase Activation in HL-60 Myeloid Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3415-3415
Author(s):  
Paul J. Shami ◽  
Vidya Udupi ◽  
Margaret Yu ◽  
Swati Malaviya ◽  
Joseph E. Saavedra ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Caspase 3 ◽  
Myelogenous Leukemia ◽  
Leukemia Cells ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Dose Dependent Fashion ◽  
Acute Myelogenous ◽  
Dose Dependent

Abstract NO induces differentiation and apoptosis in Acute Myelogenous Leukemia (AML) cells. Glutathione S-Transferases (GST) play an important role in multidrug resistance and are upregulated in 90% of AML cells. We have designed a novel prodrug class that releases NO on metabolism by GST. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antileukemic activity. We have previously shown that JS-K induces apoptosis in HL-60 cells by a caspase dependent mechanism (Molecular Cancer Therapeutics2:409-417,2003). The purpose of this study was to determine the pathway through which JS-K induces apoptosis. Western blot analysis showed that treatment of HL-60 cells with JS-K (0 – 1 μM) for 6 hours results in release of Cytochrome c from mitochondria in a dose dependent fashion. Treatment with JS-K resulted in a dose dependent activation of Caspase 9. Sixteen and 24 hours after exposure to 1 μM JS-K, Caspase 9 activity was induced by 393 ± 93% and 237 ± 13% of control, respectively (p = 0.03 at the 24 hours time point). Treatment with JS-K resulted in a dose dependent activation of Caspase 3. Twenty four hours after exposure to 1 μM JS-K, Caspase 3 activity was 208 ± 3.4 % of control (p = 0.02). Treatment with JS-K also resulted in a dose dependent activation of Caspase 8, but to a lesser extent than Caspase 9 and 3. Twenty four hours after exposure to 1 μM JS-K, Caspase 8 activity was 144 ± 5.3 % of control (p = 0.04). We conclude that JS-K activates the intrinsic pathway of apoptosis in leukemia cells by inducing the release of Cytochrome c from mitochondria. (NO1-CO-12400).

Pro-Apoptotic Effects on CLL (Chronic Lymphocytic Leukemia) of ABT-737, a Novel Fully Synthetic Bcl-2/Bcl-XL Antagonist.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 952-952 ◽  
Author(s):  
Shinichi Kitada ◽  
Edward Monosov ◽  
Sharon Chandler ◽  
Esther D. Avery ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Caspase 3 ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cell ◽  
Parp Cleavage ◽  
Healthy Individuals ◽  
B Lymphoma ◽  
Over Expression ◽  
Dose Dependent

Abstract Altered expression of Bcl-2-family protein plays a central role in apoptosis dysregulation in cancer and leukemia, promoting malignant cell expansion and contributing to chemoresistance. Anti-apoptotic Bcl-2-family proteins Bcl-2 and Bcl-XL have been thoroughly validated as drug discovery targets for cancer, and strategies for inhibiting these proteins have been devised based on mimicking their endogenous antagonists, the BH3-only proteins. CLL (chronic lymphocytic leukemia) is a quintessential example of a human malignancy caused by defective programmed cell death, representing the most common form of adult leukemia in North America and Europe. Over-expression of the Bcl-2 protein is one of the most consistent and prominent etiological factors associated with this disease. In this study, we evaluated biological effects of ABT-737, a novel fully synthetic Bcl-2/Bcl-XL antagonist developed at Abbott Laboratories, on CLL cells and B-lymphoma cell lines in vitro. ABT-737 induced a striking dose-dependent apoptosis in all CLL cells tested, with a Lethal Dose 50% (LD50) of 3–10 nM for 10 of 11 CLL samples. ABT-737 exhibited similar activity against chemo-naive cells as well as extensively treated, relapsed-disease. In contrast, an enantiomer of ABT-737 with little affinity for Bcl-2 and Bcl-XL was inactive at concentrations up to 1 μM, demonstrating specificity. Similarly, ABT-737 induced striking dose-dependent apoptosis in B-lymphoma cell lines, such as 380 lymphoma cell line which over-expressed Bcl-2 as a result of t14:18 translocation, with the LD50 ratio for ABT-737:Enantiomer control of approximately 1,000. At concentrations up to 0.1 μM, ABT-737 had no cytotoxic action on normal T-lymphocytes isolated from peripheral blood collected from healthy individuals. In addition, CLL cells were at least 10 fold more sensitive to ABT-737 than normal CD19-positive B-lymphocytes isolated from healthy individuals. Moreover, ABT-737 induced caspase 3 activation and PARP cleavage within 2 hours in CLL B-cells, while zVAD-fmk completely blocked caspase 3 activation and PARP-cleavage. The mechanism of ABT-737 was further validated by confocal time-lapsed microscopy experiments, where the active compound (but not enantiomer control) was demonstrated to displace a Green Fluorescent Protein (GFP)-tagged BH3-containing protein from wild-type Bcl-XL localized at mitochondrial surfaces in intact tumor cell lines. In contrast, active compound failed to displace GFP-BH3 protein from the mitochondrial surface of cells expressing mutants of Bcl-XL purposely engineered to be incapable of binding ABT-737. Taken together, these data strongly suggest that ABT-737 is a mechanism-based inhibitor of Bcl-2 and Bcl-XL that warrants further evaluation for the possible treatment of CLL and other malignancies linked to over-expression of Bcl-2 or Bcl-XL, where chemorefractory states represent a barrier to successful eradication of cancer.

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