Antitumor effects of lenalidomide in combination with IDEC114 (anti CD80) in lymphoma bearing severe combined immunodeficiency (SCID) mouse model

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3037-3037
Author(s):  
N. M. Reddy ◽  
F. Hernandez-Ilizalituri ◽  
J. Knight ◽  
M. S. Czuczman
Keyword(s):  
Antitumor Activity ◽  
B Cell Lymphoma ◽  
Scid Mice ◽  
Thymidine Uptake ◽  
Antitumor Effects ◽  
Raji Cells ◽  
Tail Vein ◽  
Tail Vein Injection

3037 Background: Lenalidomide is a thalidomide analogue with immunomodulatory effects. We previously demonstrated that lenalidomide enhances the biological activity of rituximab. In our current work we further studied the effects of combining lenalidomide with IDEC114, a primatized anti-CD80 monoclonal antibody, which is undergoing clinical testing in B-cell lymphoma. Methods: Raji cells were exposed in vitro to lenalidomide (10μg/ml) or DMSO over five days. Changes in DNA synthesis were determined by [3H]-thymidine uptake. For ADCC and CMC assays, lenalidomide or control exposed Raji cells were labeled to 51Cr and then exposed to IDEC114 or isotype control and PBMC’s or human serum. For in vivo studies, 6–8 week old SCID mice were inoculated with 1×106 Raji cells via tail vein injection and after a period of 72 hours animals were divided into four cohorts. Lenalidomide was administered intraperitoneally (i.p) at 0.5mg/kg/dose on days +3, +4, +8, +9, +13, +14, +18 and +19. IDEC114 was administered via tail vein injection at 10mg/kg/dose on days +5, +10, +15 and +20. Difference in survival between treatment groups was performed by Kaplan-Meier analysis. Results: In vitro exposure of Raji to lenalidomide for five consecutive days enhanced the anti-proliferative effects of IDEC114 when compared to control. In addition, an improvement in IDEC114-associated ADCC was observed in lenalidomide-exposed Raji cells. In vivo treatment of SCID mice with lenalidomide in combination with IDEC114 led to prolongation of survival (44 days) compared to either biological agent alone (p<0.01). Conclusions: Our current research demonstrates that Lenalidomide when added to IDEC114 has augmented in vitro antitumor activity (i.e, antiproliferation and ADCC) and synergistic effects in vivo (i.e., prolongation of survival). We hypothesize and currently are evaluating whether the improvement in in vivo antitumor activity of IDEC114, when combined with Lenalidomide, is secondary to potential changes in the tumor microenvironment and/or IMiD-primed upregulation of NK cells and ADCC. This promising unique combination of biologics warrants evaluation as a clinical trial. (Supported by USPHS grant PO1-CA103985 from the National Cancer Institute.) No significant financial relationships to disclose.

Lenalidomide Enhances the Biological Activity of Galiximab Against Non-Hogkin’s Lymphoma In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2353-2353
Author(s):  
Nishitha Reddy ◽  
Francisco J. Hernandez-Ilizaliturri ◽  
Joy Knight ◽  
Czuczman S. Myron ◽  
Keyword(s):  
Growth Inhibition ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Raji Cells ◽  
Isotype Control ◽  
Tail Vein Injection

Abstract Lenalidomide, a thalidomide analog, has dual anti-tumor activities against B-cell lymphomas and other hematological malignancies by inducing direct apoptosis in malignant cells and modulating the tumor microenviroment (angiogenesis inhibition) or the host immune response. We previously demonstrated that lenalidomide enhances rituximab-mediated antibody dependent cellular cytotoxicity (ADCC). In our current work we further studied the effects of combining lenalidomide with galiximab (IDEC114), a primatized anti-CD80 monoclonal antibody, which is undergoing clinical testing in B-cell lymphoma. To this end a panel of rituximab-sensitive or rituximab-resistant B-cell lymphoma cell lines was exposed in vitro to lenalidomide (10μg/ml) or DMSO (0.01%) with our without galiximab (10μg/ml) or isotype control antibody (10μg/ml) and incubated at 37°C, 5%CO2 over five days. Changes in DNA synthesis were determined by measuring [3H]-thymidine uptake at 24 and 48 hrs. To asses changes in galiximab-mediated ADCC, peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers were incubated with lenalidomide or control for 72 hrs. Subsequently, NHL cells were labeled with 51Cr and then exposed to galiximab or isotype control (10mg/ml) and PBMCs (Effector:Target ratio, 40:1). For in vivo studies, 6–8 week old SCID mice were inoculated with 1×106 Raji cells via tail vein injection and after a period of 72 hours, in order to allow for tumor engraftment, animals were divided into four cohorts (control, lenalidomide alone, galiximab alone, and lenalidomide + galiximab). Lenalidomide was administered intraperitoneally (i.p) at 0.5mg/kg/dose on days +3, +4, +8, +9, +13, +14, +18 and +19. Galiximab was administered via tail vein injection at 10mg/kg/dose on days +5, +10, +15 and +20. Difference in survival between treatment groups was performed by Kaplan-Meier analysis. Results: In vitro exposure of various NHL cells to lenalidomide for five consecutive days enhanced the anti-proliferative effects of galiximab against Raji cells (40% of growth inhibition) when compared to Galiximab (15% growth inhibition) or Lenalidomide (14% growth inhibition) at 24 hrs. Similar results were observed in other cell lines. In addition, an improvement in galiximab-associated ADCC was observed in lenalidomide-exposed NHL cells. In vivo treatment of SCID mice with lenalidomide in combination with galiximab led to prolongation of the median survival (39 days, 35–42 95% C.I.) compared to galiximab (28 days, 26–29 95% C.I.) or Lenalidomide (23 days, 22–25 95% C.I.) alone ((p&lt;0.01). Conclusions: Our current research demonstrates that Lenalidomide when added to galiximab has augmented in vitro antitumor activity (i.e, antiproliferation and ADCC) and synergistic effects in vivo (i.e., prolongation of survival compared to either monotherapy). Our promising preclinical results of the unique combination of lenalidomide plus galiximab supports future evaluation of this doublet as a clinical trial. (Supported by USPHS grant PO1-CA103985 from the National Cancer Institute.)

In Vivo Evaluation of Immunomodulating Effects of Lenalidomide (L) on Tumor Cell Microenvironment as a Possible Underlying Mechanism of the Antitumor Effects Observed in Patients (pts) with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2975-2975 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Swaminathan Padmanabhan ◽  
Kena C. Miller ◽  
Paula Pera ◽  
Laurie DiMiceli ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Antitumor Effects ◽  
Absolute Increase

Abstract Introduction: L is a more potent analogue of thalidomide with antitumor activity reported in MDS and multiple myeloma. Clinical anti-leukemic activity of L is reported for the first time by our group in pts with CLL. The underlying mechanism of its antitumor activity remains undetermined. We investigated the effect of L on the tumor microenvironment and studied the modulation of soluble cytokines and immune cells (T and NK cells) in pts receiving L. Patients and Methods: CLL pts enrolled on the clinical study with L were eligible. Pre and post (day 7) samples were obtained for evaluation of changes in serum cytokine and immune cell environment. Malignant cells were also obtained to investigate the in vitro antitumor activity of L prior to initiating treatment on clinical trial. Results: With Anexin V staining for evaluation of apoptosis induction, in vitro testing of pts samples (n=10) showed only a modest increase in apoptosis at 200mg of L - levels clinically not achievable. Yet same pts treated with L on clinical study showed significant antitumor response, suggesting the mechanism to be possibly related to modulation of the tumor microenvironment. In evaluation of the tumor cytokine microenvironment (n= 10) we noted significant L induced increase in IL-10 (n=6), IL-8 (n=8), IP-10 (n=10), IL-8 (n=8), TNF-alpha (n=4) and decrease in PDGF (n=5) and RANTES (n=5). While evaluation of the immune cell repertoire we observed an absolute increase in T-cell as well as NK-cell after treatment with L. Conclusion: Our in vitro evaluation does not suggest a direct apoptotic effect of L on the malignant CLL cells and thus support the hypothesis that the anti-leukemic effect noted in the clinical trial (reported separately) is most likely from in vivo modulation of the tumor microenvironment as is demonstrated from changes in the cytokine milieu and the cellular immune response. Collectively these changes may be responsible for the immune modulating properties of L and the resultant anti-CLL activity in pts.

Vaccine Measles Virus Has Therapeutic Potential In B Cell Malignancy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3757-3757
Author(s):  
Bella Patel ◽  
Dey Aditi ◽  
Ehsan Ghorani ◽  
Yogesh Malam ◽  
Steele Andy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Intravenous Injection ◽  
Measles Virus ◽  
Lymphocytic Leukaemia ◽  
Intratumoral Injection ◽  
Scid Mice ◽  
Prolonged Survival ◽  
Tail Vein

Abstract Abstract 3757 Replicating viruses that selectively lyse transformed cells are attractive agents for cancer therapy. The vaccine strain of measles virus has proven oncolytic activity in various murine models of malignancy including myeloma and lymphoma. These pre-clinical reports of MV efficacy have led to advanced phase clinical trial. In the study here we investigate the anti-tumour potential of MV in 2 novel disease targets:- adult B lineage acute lymphoblastic leukaemia (ALL) and Chronic lymphocytic leukaemia (CLL) using in-vitro and in-vivo models. MV derived from the Edmonston strain genetically engineered to express GFP was used to infect primary ALL (n = 6) and chronic lymphocytic leukaemia (CLL, n = 7) cells. All CLL and ALL cells expressed the MV receptor CD46 and were efficiently infected by MV-GFP as indicated by quantitation of viral nucleocapsid mRNA by RQ-PCR and immunoblotting of viral proteins N and H. Large multinucleated syncytia, characteristic of MV- induced cytopathology, were found in all infected ALL cultures, by contrast syncitium formation was much less prominent in the infected CLL specimens. Despite this, both CLL and ALL cells were efficiently killed by MV-GFP, as characterised by viability assays and immunoblotting for PARP cleavage. To further probe the contribution of cell to cell fusion in MV induced oncolysis we used a relatively non-fusogenic strain of MV:- MV-Moraten to infect CLL and ALL specimens. As expected ALL and CLL cells infected with MV-Moraten lacked the typical features of MV induced cytopathology. Despite this cell viability was markedly reduced in both ALL and CLL cultures infected with MV-Moraten compared to uninfected controls suggesting that intracellular fusion might be dispensable for MV-induced oncolysis in our two models. To test whether MV had therapeutic efficacy in-vivo we established subcutaneous xenografts of pre-B ALL in CB17/SCID mice using the Nalm-6 cell line and administered 1 × 107 pfu of MV (n==12) or UV inactivated MV (n=12) intratumorally on 10 occasions. In vivo MV administration had striking antitumour activity resulting in complete resolution of 11/12 or regression (1/12) of established subcutaneous pre-B ALL tumours by week 4. In contrast, all UV-MV treated tumours progressed. The differences in tumour growth between the MV treated and UV-MV control groups was significantly different (p < 0.0001, Figure 1). To test for MV-induced oncolysis in a model more closely related to ALL in humans we used a disseminated pre-B ALL model established by tail vein injection of 1 × 106 Nalm-6 cells. 1 × 106 pfu of MV or UV-MV was administered by the intravenous route six times. Eleven of twelve mice receiving replication competent MV remain disease free whereas 6/7 mice receiving tail vein administered UV MV had become moribund by 67 days (Figure 2). Bone marrow examination of moribund mice revealed 52 – 99% of CD19+/CD10+ Nalm-6 cells present. Overall, our data suggest that both ALL and CLL are targets for MV-mediated lysis in vitro. The significant antineoplastic activity of MV against both subcutaneous and disseminated ALL xenografts holds great promise towards developing vaccine MV as a therapeutic tool in adult ALL. Figure 1 Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Figure 1. Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Figure 2 Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Figure 2. Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Disclosures: No relevant conflicts of interest to declare.

Antitumor Activities of Extracts and Compounds from Water Decoctions of Taxus cuspidata

2010 ◽  
Vol 38 (06) ◽  
pp. 1107-1114 ◽  
Author(s):  
Shougang Jiang ◽  
Yu Zhang ◽  
Yuangang Zu ◽  
Zhuo Wang ◽  
Yujie Fu
Keyword(s):  
Antitumor Activity ◽  
Water Soluble ◽  
Taxus Cuspidata ◽  
Antitumor Activities ◽  
Antitumor Effects ◽  
Anticancer Properties ◽  
Specific Host ◽  
First Time

Water decoctions from the leaves of Taxus cuspidata are used in traditional Chinese medicine to treat cancer, suggesting that water soluble constituents from these leaves may possess anticancer properties. Interestingly, hydrophilic paclitaxel derivatives, as opposed to paclitaxel itself, can be detected by high pressure liquid chromatography in water decoctions from these leaves. The remainder extracts, which are free of paclitaxel and hydrophilic paclitaxel derivatives, from the T. cuspidata leaves were investigated for antitumor activity in vivo and in vitro for the first time in this study. EE80B, 7-xylosyl-10-deacetylpaclitaxel and 7-xylosyl-10-deacetylpaclitaxel C displayed the most antitumor activity in vivo. However, in vitro studies with tumor cell lines showed that EE80B had a significantly smaller antitumor effect than paclitaxel. We hypothesize that water decoctions from T. cuspidata leaves exhibit antitumor effects in vivo, which may be aided by the activation of specific host mechanisms (e.g. stimulation of antitumor immunity) which are not present in vitro.

scholarly journals The SMAC mimetic LCL-161 displays antitumor activity in preclinical models of rituximab-resistant B-cell lymphoma

2018 ◽  
Vol 2 (23) ◽  
pp. 3516-3525 ◽  
Author(s):  
Kyle Runckel ◽  
Matthew J. Barth ◽  
Cory Mavis ◽  
Juan J. Gu ◽  
Francisco J. Hernandez-Ilizaliturri
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Effect ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Sensitive Cell ◽  
In Vivo Models ◽  
Synergistic Enhancement

Abstract Clinical observations suggest the existence of shared resistance pathways between rituximab and chemotherapy agents. To explore the mechanisms of rituximab resistance, our group created rituximab-resistant cell lines (RRCLs), which display altered expression of several inhibitor of apoptosis (IAP) family proteins. Here, we provide evidence to support pharmacologically targeting IAPs in lymphoma with LCL-161, a small molecule mimetic of the second mitochondria-derived activator of caspases (SMAC). The antitumor effect of LCL-161 was determined using luminescent adenosine triphosphate assays, flow cytometry, SCID mouse xenografts, and ex vivo patient biopsy sample studies. In vitro exposure to LCL-161 also resulted in a dose-dependent decrease in IAP levels, along with synergistic enhancement of the antitumor effect of cytotoxic chemotherapy, in rituximab-sensitive cell lines and RRCLs. In addition, LCL-161 increased the cytotoxic effect of the proteasome inhibitor carfilzomib in ex vivo lymphoma patient samples. The combination of LCL-161 with the chemotherapy regimen rituximab, gemcitabine, and vinorelbine (RGV) improved in vivo survival compared with RGV alone in severe combined immunodeficient mice implanted with RRCLs but not in animals implanted with rituximab-sensitive cell lines. In summary, LCL-161 exhibits synergistic antitumor activity in both in vitro and in vivo models of resistant lymphoma. Our data support further preclinical investigation of LCL-161 as a novel antilymphoma agent.

Interrogating resistance mechanisms to PD-1 blockade therapy with CRISPR.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3077-3077
Author(s):  
Davis Yuri Torrejon ◽  
Jesse Meir Zaretsky ◽  
Daniel Sanghoon Shin ◽  
Mykola Onyshchenko ◽  
Gabriel Abril-Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cell Line ◽  
Wild Type ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Syngeneic Mouse Model

3077 Background: We tested the biological significance of the loss of function (LOF) mutations in JAK1 or JAK2 within the IFN-receptor-pathway and in beta-2-microglobulin (B2M), which had been found in patient biopsies with resistance to anti-PD-1 therapy. Methods: We used CRISPR/Cas9 genome editing to generate JAK1, JAK2 and B2M knockout (KO) sublines of HLA-A*02:01 MART-1 or NY-ESO-1 positive human melanoma cell lines, tested using in-vitro T cell co-culture systems and in a syngeneic mouse model (MC38) to analyze the in-vivo antitumor activity with anti-PD1 therapy. Results: The JAK2-KO cell line was insensitive to IFN-gamma induced signaling and growth arrest (p < 0.001 compared with IFN-alpha or beta), while the JAK1-KO cell line was insensitive to all three IFNs. Baseline MHC class I expression after JAK1-KO was unaffected (baseline-MFI 1230 JAK1-KO vs 1570 parental, p = 0.66), but the magnitude of change was lower upon IFN-gamma exposure compared to the parental (MFI change with IFN-gamma, 26% decrease for JAK1-KO vs 50% increase for parental). There was no difference in in-vitro cytotoxicity by NY-ESO-1-TCR transgenic T-cells against JAK1-KO-NY-ESO-1+ melanoma cells compared to the parental (78% vs 82% cytotoxicity at 10:1 E:T ratio, p NS). However, B2M-KO was resistant to killing by MART-1 specific T-cells (2% vs 96% cytotoxicity at 10:1 E:T ratio, p < 0.0001). On the other hand, in the MC38 model the significant antitumor activity of anti-PD-1 against the wild type cells was lost in both JAK2-KO and B2M-KO. The percentage of CD8+ T cells has a trend of increase with anti-PD1 compared to untreated in the MC38 wild type (p = 0.1 d12), and a trend of decrease in MC38 B2M-KO (p = 0.2 d12), but no change in JAK2-KO tumors (p = 0.7 d12). Conclusions: JAK1/2 LOF mutations result in insensitivity to IFN induced antitumor effects, but does not impair T cell recognition and cytotoxicity, while B2M LOF results in lack of antigen presentation to T cells and loss of antitumor activity. However both lead to in-vivo resistance to anti-PD-1 therapy, suggesting they do so by independent mechanisms.

The Effect of Iodine-131-Rituximab on B Cell Lymphoma In Vitro and In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4512-4512
Author(s):  
Rongcheng Luo ◽  
Qiang Zuo ◽  
Li Wei ◽  
Wangjun Liang ◽  
Dayong Zhen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Raji Cell ◽  
B Cell Lymphoma ◽  
Lethal Effect ◽  
Dependent Manner ◽  
Raji Cells ◽  
Iodine 131

Abstract The purpose of this study was to investigate the cell specific cytotoxic effect of Iodine-131 Rituximab on CD20-positive B cell lymphoma in vitro and on Raji cell tumors grown in vivo. Rituximab was labeled with Iodine -131 by the iodogen method. Cultured Raji cells or the nude mice bearing Raji tumors were treated with various concentrations of Iodine-131-Rituximab or Iodine-131 alone or Rituximab alone. The results showed that The lethal effect was found on Raji cells treated with Iodine-131-Rituximab in a dose-dependent manner; The proliferation rate of Raji cells was significantly lower in cells treated with Iodine-131-Rituximab, as compared to the cells treated with Iodine-131or Rituximab alone (P<0.05); Tumor inhibition was found to be greatest in the mice treated with Iodine-131-Rituximab through intratumor injection, as compared with Iodine-131-Rituximab i.p. injection or Rituximab alone (p<0.05). We conclude that Iodine-131-Rituximab specifically inhibits the growth of Raji tumor cells in vitro and in vivo. Iodine-131-Rituximab is a promising agent for radioimmunotherapy that targets CD20-positive B cell lymphoma.

Preclinical Rationale for the Use of the Multikinase Inhibitor Sorafenib in the Treatment of Human Lymphomas

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2605-2605
Author(s):  
Carmelo Carlo-Stella ◽  
Cristiana Lavazza ◽  
Arianna Giacomini ◽  
Loredana Cleris ◽  
Daniela Sia ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Scid Mice ◽  
Multikinase Inhibitor ◽  
Preclinical Data

Abstract Introduction: The multikinase inhibitor Sorafenib (Nexavar, Bayer) exerts a remarkable activity against a variety of nonhematological tumors by blocking tumor cell proliferation and angiogenesis through the inhibition of the RAF/MEK/ERK pathway, as well as the receptor tyrosine kinases vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), c-KIT, Flt3, and RET. Several lines of evidence suggest that sorafenib might have a relevant clinical impact in the therapy of malignant lymphomas by overcoming the cytoprotective effects of ERK, Mcl-1, and Bcl-XL. However, preclinical data establishing a rationale for the clinical use of sorafenib in lymphomas are still lacking. The present studies aimed to investigate the activity and the mechanism(s) of action of sorafenib in human lymphomas. Methods: The effects of sorafenib were evaluated in vitro using a panel of six human cell lines of different phenotypes, including JVM-2 (B-Chronic Lymphocytic Leukemia), Granta-519 (Mantle Cell Lymphoma), DOHH2 (Follicular Lymphoma), SU-DHL-4V (Diffuse Large B-Cell Lymphoma), HD-MY-Z (Hodgkin Lymphoma), and KMS-11 (Multiple Myeloma) cell lines. Additionally, the antitumor efficacy and mechanism of action of sorafenib were investigated in vivo by means of five lymphoma xenograft models in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Results: In vitro, the response of cell lines to sorafenib (1–10 μM for 24–48 hours) was evaluated by detecting apoptotic cell death with the annexin-V/propidium iodide double staining assay, and viable cell countings with the Trypan blue dye exclusion test. All 6 cell lines responded to sorafenib with values of 50% inhibitory concentrations ranging from 1 to 7.5 μM. In contrast, normal CD34+ cells remain insensitive to the drug up to 15 μM. Despite significant rates of sorafenib-induced apoptosis were seen in all cell lines, activation of caspase-3 analyzed by fluorescent-activated cell sorter was only detected in DOHH-2 and JVM-2 cell lines. The phosphorylation status of mitogen-activated protein kinase (MAPK) was investigated using the human phospho-MAPK Array kit (R&D systems), analyzed with the open source imaging software ImageJ (http://rsb.info.nih.gov/ij/), and then validated by Western blotting. Sorafenib induced a significant reduction of pAkt1, pAkt2, and pAkt3 in SU-DHL-4V, Granta-519, and JVM-2 cell lines, whereas p38 phosphorylation levels were significantly reduced in all but one cell line (KMS-11). Reduced levels of pMEK, pERK1 and pERK2 were detected in SU-DHL-4V, KMS-11, Granta-519, and HD-MY-Z cell lines. Down-regulation of MCL-1 was seen in HD-MY-Z, JVM-2, and DOHH-2 cell lines. In vivo, the activity of sorafenib was evaluated in NOD/SCID mice bearing subcutaneous tumor nodules. Animals with tumors averaging from 140 to 160 mg were randomly grouped to receive sorafenib (90 mg/kg body weight, IP, once daily for 15 days) or control vehicle. Sorafenib significantly (P ≤0.001) reduced the growth of subcutaneous HD-MY-Z, KMS-11, Granta-519, SU-DHL-4V, and JVM-2 nodules, with values of tumor growth inhibition of 70%, 52%, 40%, 37%, and 24%, respectively. In control mice, TUNEL staining of tumor sections showed large areas of viable cells without significant necrosis, whereas a 2- to 5-fold increase of necrotic areas was detected in sorafenib-treated mice bearing the different lymphoma xenografts. Analysis of tumor vasculature by means of in vivo biotinylation of endothelial cells with sulfo-NHS-LC-biotin showed a 30% to 60% reduction of vessel density in sorafenib-treated mice bearing the different lymphoma xenografts. Conclusions: Sorafenib efficiently targets a variety of human lymphomas representative of different phenotypes by inhibiting tumor angiogenesis and directly affecting tumor cell survival. Our preclinical data establish a rationale for exploring the clinical activity of sorafenib in human lymphomas.

Bufalin inhibits human diffuse large B-cell lymphoma tumorigenesis by inducing cell death through the Ca2+/NFATC1/cMYC pathway

2020 ◽  
Author(s):  
Jincheng Song ◽  
Dan Zou ◽  
Xiaoxuan Zhao ◽  
Yang Chen ◽  
Fei Lv ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dependent Manner ◽  
Multiple Cancer ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL.

scholarly journals Selectively Targeting Tumor Hypoxia with the Hypoxia-Activated Prodrug CP-506

2021 ◽  
Author(s):  
Alexander M.A. van der Wiel ◽  
Victoria Jackson-Patel ◽  
Raymon Niemans ◽  
Ala Yaromina ◽  
Emily Liu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Hypoxia ◽  
Human Tumor ◽  
Tumor Oxygenation ◽  
Antitumor Effects ◽  
Wide Range ◽  
Hypoxic Tumor

Abstract Background Hypoxia-activated prodrugs (HAPs) are a promising class of antineoplastic agents that can selectively eliminate hypoxic tumor cells. The present study evaluates the hypoxia-selectivity and antitumor activity of CP-506, a DNA alkylating HAP with favorable pharmacological properties. Methods Stoichiometry of reduction, one-electron affinity, and back-oxidation rate of CP-506 were characterized by fast-reaction radiolytic methods. In vitro, 2D monolayer and 3D spheroid and multicellular layer cultures were used to investigate the hypoxia-selectivity of CP-506. In vivo, the causal relationship between tumor oxygenation and antitumor effects of CP-506 was assessed. Mice bearing a range of human tumor xenografts were exposed to CP-506 and tumor growth was monitored. A multivariate linear regression model was used to identify factors associated with CP-506 treatment outcome. Results Net reduction, metabolism, and cytotoxicity of CP-506 were maximally inhibited at oxygen concentrations above 1 µM (0.1% O2). CP-506 demonstrated cytotoxicity selectively in hypoxic 2D and 3D cell cultures with normoxic/anoxic IC50 ratios up to 203. In vivo, the antitumor effects of CP-506 were selective for hypoxic tumor cells and causally related to tumor oxygenation. CP-506 effectively decreased the hypoxic fraction and inhibited growth of a wide range of hypoxic xenografts. Two well-oxygenated models were refractory to treatment despite intrinsic anoxic sensitivity in vitro. A multivariate regression analysis revealed baseline tumor hypoxia and in vitro sensitivity to CP-506 to significantly correlate with treatment response. Conclusions Our results demonstrate that CP-506 selectively sterilizes hypoxic tumor cells and has broad antitumor activity. Our data also indicate that tumor hypoxia and cellular sensitivity to CP-506 are strong determinants of the antitumor effects of CP-506.

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