Sensitivity to antineoplastic agents of human tumor strains in immunodeficient mice

1994 ◽  
Vol 118 (3) ◽  
pp. 1000-1001
Author(s):  
I. K. Bukharova ◽  
E. S. Revazova ◽  
L. V. Moroz
Keyword(s):  
Antineoplastic Agents ◽  
Human Tumor ◽  
Immunodeficient Mice ◽  
Human Tumor Strains

scholarly journals Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 85 ◽  
Author(s):  
Jesus Luna ◽  
Steven Grossenbacher ◽  
Ian Sturgill ◽  
Erik Ames ◽  
Sean Judge ◽  
...  
Keyword(s):  
Stem Cell ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Human Tumor ◽  
Growth Delay ◽  
Cell Targeting ◽  
Immunodeficient Mice

Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.

The Use of Congenitally Immunodeficient Mice to Study Human Tumor Metastases and Immunotherapy

1992 ◽  
Vol 12 (3) ◽  
pp. 196-198 ◽  
Author(s):  
James J. Mul?? ◽  
Douglas L. Jicha ◽  
Steven A. Rosenberg
Keyword(s):  
Human Tumor ◽  
Immunodeficient Mice ◽  
Tumor Metastases

scholarly journals Systematic analysis of the human tumor cell binding to human vs. murine E- and P-selectin under static vs. dynamic conditions

Glycobiology ◽  
2020 ◽  
Vol 30 (9) ◽  
pp. 695-709 ◽  
Author(s):  
Sarah Starzonek ◽  
Hanna Maar ◽  
Vera Labitzky ◽  
Daniel Wicklein ◽  
Charlotte Rossdam ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Human Tumor ◽  
Sialyl Lewis X ◽  
Metastasis Formation ◽  
Human Tumor Cells ◽  
Systematic Analysis ◽  
Dynamic Conditions ◽  
Immunodeficient Mice ◽  
Static Conditions

Abstract Endothelial E- and P-selectins promote metastasis formation by interacting with sialyl-Lewis X and A (sLeX/sLeA) on circulating tumor cells. This interaction precedes extravasation and can take place under dynamic and static conditions. Metastasis formation is often studied in xenograft models. However, it is unclear whether species differences exist in the ligand specificity of human (h) vs. murine (m) selectins and whether different ligands are functional under dynamic vs. static conditions. We systematically compared the h vs. m E- and P-selectin (ESel/PSel) binding of a range of human tumor cells under dynamic vs. static conditions. The tumor cells were categorized by their sLeA/X status (sLeA+/sLeX+, sLeA−/sLeX+ and sLeA−/sLeX−). The general biological nature of the tumor–selectin interaction was analyzed by applying several tumor cell treatments (anti-sLeA/X blockade, neuraminidase, pronase and inhibition of O/N-glycosylation). We observed remarkable differences in the static vs. dynamic interaction of tumor cells with h vs. m ESel/PSel depending on their sLeA/X status. The tumor cell treatments mostly affected either static or dynamic as well as either h- or m-selectin interaction. mESel showed a higher diversity of potential ligands than hESel. Inhibition of O-GalNAc-glycosylation also affected glycosphingolipid synthesis. Summarized, different ligands on human tumor cells are functional under static vs. dynamic conditions and for the interaction with human vs. murine ESel/PSel. Non-canonical selectin ligands lacking the sLeA/X glycan epitopes exist on human tumor cells. These findings have important implications for the current development of glycomimetic, antimetastatic drugs and encourage the development of immunodeficient mice with humanized selectins.

scholarly journals Patient-Derived Xenograft Models in Gynecologic Malignancies

2014 ◽  
pp. e258-e266 ◽  
Author(s):  
Clare L. Scott ◽  
Helen J. Mackay ◽  
Paul Haluska
Keyword(s):  
Targeted Therapies ◽  
Human Tumor ◽  
High Rate ◽  
Gene Copy ◽  
Great Promise ◽  
Novel Therapies ◽  
Gynecologic Malignancies ◽  
Variable Response ◽  
Immunodeficient Mice

In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types—ovarian, uterine, and cervical—are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies. Patient-derived xenografts (PDX) generated from fresh human tumor without prior in vitro culture, combined with whole genome expression, gene copy number, and sequencing analyses, could dramatically aid the development of novel therapies for gynecologic malignancies. Gynecologic tumors can be engrafted in immunodeficient mice with a high rate of success and within a reasonable time frame. The resulting PDX accurately recapitulates the patient's tumor with respect to histologic, molecular, and in vivo treatment response characteristics. Orthotopic PDX develop complications relevant to the clinic, such as ascites and bowel obstruction, providing opportunities to understand the biology of these clinical problems. Thus, PDX have great promise for improved understanding of gynecologic malignancies, serve as better models for designing novel therapies and clinical trials, and could underpin individualized, directed therapy for patients from whom such models have been established.

scholarly journals Synthesis and Cytotoxicity of Cyanoborane Adducts of N6-Benzoyladenine and 6-Triphenylphosphonylpurine

2002 ◽  
Vol 9 (1-2) ◽  
pp. 19-32 ◽  
Author(s):  
Tanya C. Scarlett ◽  
Richard W. Durham ◽  
Iris H. Hall ◽  
Richard J. Crosswicks ◽  
Joshua D. Berkowitz ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Antineoplastic Agents ◽  
Topoisomerase I ◽  
Reductase Activity ◽  
Human Tumor ◽  
Acute Monocytic Leukemia ◽  
Human Leukemia ◽  
Monocytic Leukemia ◽  
Dna And Rna ◽  
Dna Strands

N6-Benzoyladenine-cyanoborane (2), and 6-triphenylphosphonylpurine-cyanoborane (3) were selected for investigation of cytotoxicity in murine and human tumor cell lines, effects on human HL-60 leukemic metabolism and DNA strand scission to determine the feasibility of these compounds as clinical antineoplastic agents. Compounds 2 and 3 both showed effective cytotoxicity based on ED50 values less than 4 μg/ml for L1210, P388, HL-60, Tmolt3, HUT-78, HeLa-S3 uterine, ileum HCT-8, and liver Hepe-2. Compound 2 had activity against ovary 1-A9, while compound 3 was only active against prostate PL and glioma UM. Neither compound was active against the growth of lung 549, breast MCF-7, osteosarcoma HSO, melanoma SK2, KB nasopharynx, and THP-1 acute monocytic leukemia. In mode of action studies in human leukemia HL-60 cells, both compounds demonstrated inhibition of DNA and protein syntheses after 60 min at 100 μM. These compounds inhibited RNA synthesis to a lesser extent. The utilization of the DNA template was suppressed by the compounds as determined by inhibition of the activities of DNA polymerase α, m-RNA polymerase, r-RNA polymerase and t-RNA polymerase, which would cause adequate inhibition of the synthesis of both DNA and RNA. Both compounds markedly inhibited dihydrofolate reductase activity, especially in compound 2. The compounds appeared to have caused cross-linking of the DNA strands after 24 hr at 100 μM in HL-60 cells, which was consistent with the observed increased in ct-DNA viscosity after 24 hr at 100 μM. The compounds had no inhibitory effects on DNA topoisomerase I and II activities or DNA-protein linked breaks. Neither compound interacted with the DNA molecule itself through alkylation of the nucleotide bases nor caused DNA interculation between base pairs. Overall, these antineoplastic agents caused reduction of DNA and protein replication, which would lead to killing of cancer cells.

scholarly journals Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade

2021 ◽  
Vol 118 (7) ◽  
pp. e2018690118
Author(s):  
François Moisan ◽  
Sandra Oucherif ◽  
Priscilla Kaulanjan-Checkmodine ◽  
Sorilla Prey ◽  
Benoît Rousseau ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Critical Role ◽  
Water Channel ◽  
Human Tumor ◽  
Migration And Invasion ◽  
Beta Blockade ◽  
Tumor Growth Inhibition ◽  
Tumor Cell Migration ◽  
Immunodeficient Mice ◽  
Aquaporin 1

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

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