scholarly journals Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms

Oncotarget ◽  
2017 ◽  
Vol 8 (19) ◽  
pp. 31478-31493 ◽  
Author(s):  
Tri Nguyen ◽  
Rebecca Parker ◽  
Elisa Hawkins ◽  
Beata Holkova ◽  
Victor Yazbeck ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Hdac Inhibitors ◽  
Hodgkin's Lymphoma ◽  
Lymphoma Cells ◽  
Synergistic Interactions ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

scholarly journals Adhesion to high endothelial venules: a model for dissemination mechanisms in non-Hodgkin's lymphoma

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 262-267 ◽  
Author(s):  
R Stauder ◽  
S Hamader ◽  
B Fasching ◽  
G Kemmler ◽  
J Thaler ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Lymphoma Cells ◽  
High Endothelial Venules ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Human Lymphoma ◽  
Binet Stage

The interaction of human lymphoma cells with high endothelial venules (HEVs) on sections of lymphatic tissues was studied in 44 cases of non- Hodgkin's lymphoma (NHL) with the in vitro HEV binding assay. The relative adherence ratio (RAR) of lymphoma cells to HEVs as related to that of reactive lymphocytes was 0.29 to 4.64 in 38 cases of B chronic lymphocytic leukemia (CLL), 1.15 and 1.54 in two cases of immunocytic NHL, 1.12 and 0.70 in two cases of centrocytic NHL, 1.98 in one case of a peripheral T-NHL, whereas plasma cell leukemia cells adhered very weakly (RAR 0.1). Among the patients suffering from CLL a pronounced HEV binding ability of tumor cells correlated significantly with the more unfavorable Binet stages B and C (median 1.32) as well as with a widespread lymphatic dissemination, which strongly indicates a hematogenous, HEV-mediated spread (median 1.34). In contrast, weak adherence to HEVs was associated with Binet stage A (median 0.85; P < .05) and with a lacking or only localized clinical involvement of lymph nodes (median 0.84; P < .01). Thus, specific HEV recognition processes even operate in lymphoid neoplasms and via this mechanism seem to influence the dissemination of tumors.

Construction and Characterization of a Novel Ribonuclease Immunotoxin Consisting of Two Ranpirnase (Rap) Molecules Fused to an Internalizing Anti-CD74 Humanized IgG4 Antibody.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3289-3289
Author(s):  
Sailaja S. Vanama ◽  
Puja Sapra ◽  
Hans J. Hansen ◽  
Ivan D. Horak ◽  
David M. Goldenberg ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Xenograft Model ◽  
Hodgkin's Lymphoma ◽  
Light Chains ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Sds Page

Abstract Ranpirnase (Rap), isolated from frog (Rana pipiens) oocytes, is a monomeric ribonuclease (MW 11800) that kills cells by degrading t-RNA upon internalization. Previous studies indicated that the cytotoxicity of Rap could be enhanced more than 10,000-fold when the enzyme is chemically conjugated to an internalizing antibody. Here we describe the construction and characterization of 2L-Rap-hLL1-γ4P, composed of two Rap molecules fused to hLL1, an internalizing anti-CD74 humanized monoclonal antibody. To reduce unwanted cytotoxicity, the IgG1 constant region of hLL1 was replaced with an IgG4 that contains a proline mutation in the hinge region. The Rap gene was inserted at the N-terminus of the light chain in the expression vector of hLL1 and expressed in NS0 mouse myeloma cells. The fusion protein was characterized by a variety of techniques, including SE-HPLC, SDS-PAGE, in vitro transcription translation (IVTT) assay using luciferase reporter system, and competition ELISA to measure the binding affinity for CD74. The in vitro potency was determined in non-Hodgkin’s lymphoma (Daudi) and multiple myeloma (MC/CAR) cell lines by MTS tetrazolium dye reduction assay. In vivo pharmacokinetics and biodistribution of radiolabeled 2L-Rap-hLL1- γ4P was compared to radiolabeled hLL1 mAb in naïve mice and in vivo therapeutic efficacy of 2L-Rap-hLL1- γ4P was determined in a xenograft model of Burkitt’s non-Hodgkin’s lymphoma (Daudi). Purified 2L-Rap-hLL1- γ4P was shown to be a single peak by SE-HPLC and its MW determined by MALDI-TOF to be 177,150, which is in agreement with the MW of one IgG (150,000) plus two Rap molecules (24,000). Reducing-SDS-PAGE of 2L-Rap-hLL1- γ4P revealed the presence of 3 bands, one corresponding to the heavy chain and the other two appearing to be derived from the Rap-fused light chains (38,526 and 36,700 by MS). Occurrence of the 2 light chains was shown to be due to glycosylation of Rap at the N69 residue. The binding affinity of 2L-Rap-hLL1- γ4P for CD74 was indistinguishable from that of hLL1. Both 2L-Rap-hLL1- γ4P and hLL1 bound to CD74 with subnanomolar affinity. The EC50 of RNase activity, as measured by the IVTT assay, was 300 pM for 2L-Rap-hLL1- γ4P and 30 pM for recombinant Rap (expressed in E. coil). In in vitro cytotoxicity assays, 2L-Rap-hLL1- γ4P was significantly cytotoxic against Daudi (EC50 280 pM) and the myeloma cell line, MC/CAR (EC50 50 nM). In contrast, free Rap or naked hLL1 did not demonstrate significant cytotoxicity at the concentrations tested. In vivo, the pharmacokinetic profile of 2L-Rap-hLL1- γ4P was almost identical to that of naked hLL1. Both 2L-Rap-hLL1- γ4P and hLL1 showed biphasic clearance from the circulation; the α and β half-life (t1/2) of 2L-Rap-hLL1- γ4P were 5 h and 119 h, respectively, and those of hLL1 were 4 h and 125 h, respectively. In tissue biodistribution studies, no significant difference was observed between 2L-Rap-hLL1- γ4P and hLL1 with regards to normal tissue uptake. Early efficacy results in the Daudi Burkitt’s non-Hodgkin’s lymphoma xenograft model demonstrate that treatment with a single dose of 2L-Rap-hLL1- γ4P as low as 1 μg/mouse significantly improves survival in comparison to untreated control mice (P<0.0001).

Synthetic 15-mer Peptide (PCK3145) Derived from Prostate Secretory Protein with In Vitro and In Vivo Activity Against Non-Hodgkin’s Lymphoma and Other Hematologic Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1388-1388
Author(s):  
Mireille Guerin ◽  
Cynthia Therien ◽  
Gorazd Krosl ◽  
Jinzi J. Wu ◽  
Helene Dulude ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Tumour Growth ◽  
Hematologic Malignancies ◽  
Secretory Protein ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Anti Tumor Activity

Abstract Prostate secretory protein 94 (PSP-94) has been shown to exert anti-tumor activity against prostate cancer cells, particularly in the form of PCK3145, a synthetic peptide corresponding to amino acids 31–45 of PSP-94. Indeed, when tested in a murine model, this peptide could reduce experimental prostate tumour growth. In addition, when evaluated in a Phase I clinical study, this peptide demonstrated a particularly interesting safety profile, with almost complete lack of toxicity. In order to determine whether PCK3145 could exert cytotoxic activity against other marrow infiltrating cancers, we tested its activity both in vitro and in vivo against non-Hodgkin’s lymphoma (NHL) and other hematologic cancers. Interestingly, PCK3145 inhibited the proliferation of human NHL (SR) and myeloma (RPMI-8226) cell lines in vitro. To explore its anti-tumor activity in vivo, the impact of PCK3145 was also measured by inoculating P815 malignant cells into syngeneic DBA mice. First, four groups of 6 DBA mice were injected subcutaneously with 2x104 P815 cells and then treated with subcutaneous injections of PCK3145, and compared to a peptide with the scrambled amino acid sequence, PCK5266 (peptide derived from amino acids 52 to 66 of PSP-94), and phosphate-buffered saline (PBS). Treatment with PCK3145 significantly decreased the growth of P815 tumours in comparison to PBS (p<0.001), scrambled peptide (p<0.05) and PCK5266 (p<0.01), confirming in vivo anti-tumor activity and suggesting that tumour growth inhibition is due to the specific amino acid sequence of PCK3145. The same model was used to determine the effect of PCK3145 on metastatic dissemination following intraperitoneal administration of the peptide. PCK3145 treatment led to a decreased number of liver metastasis compared to PBS (p<0.05) and scrambled peptide (p<0.05) controls. In order to determine whether PCK3145 exerted its activity by altering metalloproteinase release, metalloproteinase MMP-9 levels were measured 3 weeks post-tumor cell exposure. MMP-9 levels, measured by ELISA, in the peripheral blood of treated P815 bearing mice were similar to those obtained with healthy animals (12.83±1.890 (mean±SD) ng/ml and 7.183±0.4070 ng/ml, respectively), while MMP-9 levels were elevated in mice treated with PBS and scrambled peptide (35.12±8.559 ng/ml and 22.60±3.944 ng/ml, respectively; p<0.05). We next tested PCK3145 treatment on human SR lymphoma cell line grown subcutaneously in NOD/SCID mice. Similarly to results obtained with murine tumors, treatment with PKC3145 resulted in significant inhibition of SR non-Hodgkin’s lymphoma growth compared to treatment with PBS (p<0.001) and scrambled peptide (p<0.01). These results demonstrate that in vivo treatment with PCK3145 can reduce tumor cell proliferation of both murine and human hematologic cancers. In addition, PCK3145 has the potential to inhibit tumor cells dissemination by lowering MMP-9 secretion. Thus, PCK3145 represents a unique peptide demonstrating sequence-specific anti-tumor activity against NHL and other hematologic malignancies. Based on these results, clinical studies are being designed to evaluate its therapeutic activity in humans.

scholarly journals Bicelin (B-cell lymphoma 2 inhibitor) a Highly Safe DNA-based Anti-cancer Drug Showed No in vivo Cytopenia, Nephrotoxicity and/or Hepatotoxicity

2020 ◽  
Author(s):  
Reza Sheikhnejad ◽  
Farzaneh Ashrafi ◽  
Ardeshir Talebi ◽  
Bahar Mazaheri ◽  
Fatemeh Moslemi ◽  
...  
Keyword(s):  
Side Effects ◽  
Hodgkin’S Lymphoma ◽  
B Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Cancer Drug ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Liver Tissues

Abstract Background: Non-Hodgkin's lymphoma is the seventh most common cancer in clinic. Lymphoma could be treated with newly developed anti-apoptotic small molecule inhibitors of bcl-2 such as ABT-199 or venetoclax. However most small molecules present numerous side effects and cancer becomes resistance to them rapidly. PNT100 is a DNA-based bcl-2 inhibitor that has shown great efficacy and safety in treating non-Hodgkin's lymphoma tumors. However, liposomal carrier(smarticles) that was used to deliver PNT100 eventually failed to produce robust efficacy in the latest clinical trial conducted by ProNai Therapeutics (now called Sierra Technology). The high cost of liposomal carriers, makes this targeted drug less affordable. In addition, the liposomal components may also present some minor side effects as reported in pilot phase II trial [17-22]. In this study, we eliminated liposome and used a specific Epigenic modification to deliver this 24bp oligonucleotides (PNT100) without using additional chemicals and named it Bicelin. Methods: In this study, the safety of Bicelin was determined by evaluating the cytopenia, nephrotoxicity and hepatotoxicity effects of this drug in healthy animal model (Rats). The rats in experimental group were received Bicelin (20 mg/kg/day) for 5 days a week. The treatment was continued for 3 consecutive weeks. The blood and urine samples were collected for evaluation and the rats were then sacrificed. The kidneys and liver tissues were fixed in formalin 10% to perform histological investigation using H&E staining. Results: The in vitro and in vivo results clearly demonstrate that Bicelin is target specific and highly safe. We observed no cytopenia when blood tests were performed after 15 consecutive injection of Bicelin; Urine analysis revealed no significant differences between experimental and control group and there was no nephrotoxicity or hepatotoxicity when kidney and liver tissues were examined. Conclusion: based on our in vitro and in vivo safety studies, our bcl2 inhibitor, Bicelin is much safer and about 10-fold more effective than its liposomal form (PNT2258). Considering preclinical, phase I and II studies of PNT2258, Bicelin is expected to be very safe and effective in clinic.

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