scholarly journals Au Catalyzing Control Release NO in vivo and Tumor Growth-Inhibiting Effect in Chemo-Photothermal Combination Therapy

2021 ◽  
Vol Volume 16 ◽  
pp. 2501-2513
Author(s):  
Ying Zhang ◽  
Tianfu Zhou ◽  
Jian Li ◽  
Nuo Xu ◽  
Mingze Cai ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tumor Growth ◽  
Control Release ◽  
Inhibiting Effect ◽  
Growth Inhibiting

scholarly journals Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1844-1844
Author(s):  
John Richards ◽  
Myriam N Bouchlaka ◽  
Robyn J Puro ◽  
Ben J Capoccia ◽  
Ronald R Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Cells ◽  
Tumor Growth Inhibition ◽  
Employment Equity ◽  
Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

Therapeutic Efficacy and Cure Of Sensitive and T315I Pan-Resistant Human Ph+ Leukemia In Mice Using a TCR-Like Antibody To WT1/HLA-A0201 Alone, Or In Combination With Tyrosine Kinase Inhibitors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 855-855
Author(s):  
Leonid Dubrovsky ◽  
Elliott Brea ◽  
Dmitry Pankov ◽  
Nicholas Veomett ◽  
Tao Dao ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Cell Line ◽  
Wilms Tumor ◽  
High Dose ◽  
Human Leukemia ◽  
Rt Pcr

Abstract Acute and chronic leukemias, including CD34+ CML stem cells, overexpress the Wilms tumor gene 1 (WT1) protein, making WT1 an attractive therapeutic target. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201, allowing it to target an undruggable, widely expressed, intracellular oncogene product. BV173 is an HLA-A0201+, human Ph+ ALL cell line that expresses WT1, and tagged by our lab with luciferase. We engineered a tyrosine kinase inhibitor (TKI) resistant BV173-R cell line by transducing BV173 with the resistant T315I Bcr-Abl plasmid. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. Tumor growth in vivo was assessed in NOD/SCID gamma (NSG) mice with bioluminescence imaging (BLI). RT-PCR was used to evaluate minimal residual disease in mice with negative BLI signal at the end of therapy. Imatinib, dasatinib, and ponatinib were used at up to maximally tolerated doses, given IP once daily. ESKM was administered at 100 µg twice weekly IP. ESKM mediated ADCC against both BV173 and BV173-R cell lines in vitro. In a BV173 engrafted human leukemia xenograft model, ESKM was more potent than imatinib, with median tumor growth reduction of 78% vs 52%. Combination of imatinib and ESKM therapy resulted in a 94% reduction in leukemic growth. High dose dasatinib (40 mg/kg daily) was more potent than ESKM, but discontinuation of therapy due to dasatinib toxicity resulted in relapse. Combination with ESKM therapy with dasatinib resulted in cure in 75% of mice, confirmed by bone marrow RT-PCR three weeks after termination of therapy. For mice cytoreduced with dasatinib followed by consolidation therapy with ESKM, delayed relapse was observed, but no cures. ESKM was highly superior to imatinib and dasatinib against the T315I BV173-R leukemia in vivo. Cures were not achieved with combination therapy of ESKM and either first or second generation TKIs against resistant T315I leukemia. Ponatinib at 10 mg/kg had higher efficacy than ESKM alone against BV173-R, but mice treated with combination of ESKM and ponatinib had superior tumor reduction. CONCLUSION: ESKM is an effective therapeutic antibody for sensitive and T315I Ph+ ALL. Resistant T315I Ph+ leukemic growth is inhibited more effectively by ESKM therapy compared to imatinib and dasatinib, and combination therapy with ESKM is superior to ponatinib. Supported by the Leukemia and Lymphoma Society, NIH R01CA55349, P01 23766 and T32CA62948-18. Disclosures: Yan: Eureka Therapeutics: Employment. Liu:Eureka Therapeutics: Employment, Equity Ownership.

Combination therapy of zibotentan with cisplatinum and paclitaxel is an effective regimen for epithelial ovarian cancerThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (6) ◽  
pp. 676-681 ◽  
Author(s):  
Laura Rosanò ◽  
Roberta Cianfrocca ◽  
Francesca Spinella ◽  
Valeriana Di Castro ◽  
Pier Giorgio Natali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Standard Of Care ◽  
Tumor Grade ◽  
Proliferation Index ◽  
Clinical Trial Results

In human ovarian carcinoma, the endothelin-1 (ET-1) / endothelin A receptor (ETAR) axis is overexpressed, correlating with tumor grade. Moreover, ETAR activation by ET-1 affects cell proliferation, survival, angiogenesis, and invasion. ETAR blockade with zibotentan (ZD4054), a specific ETAR antagonist, significantly inhibits ovarian cancer growth in vitro and in vivo, underscoring the relevance of this pathway as a target for cancer therapy. Since clinical trial results have defined the combination of platinum and taxane as the standard of care in the management of ovarian cancer, here we explored the therapeutic efficacy of the integration of zibotentan with cytotoxic drugs having different modes of action. We found that the combination of zibotentan with cisplatinum as well as zibotentan with paclitaxel was more effective at inhibiting ovarian cancer HEY cell proliferation induced by endogenous ET-1 than were the single agents alone. However, a significantly enhanced efficacy was observed when we combined zibotentan, cisplatinum, and paclitaxel. Accordingly, in HEY xenografts the coadministration of zibotentan with cisplatinum enhanced the efficacy of the cytotoxic drug alone in controlling tumor growth, associated with reduction in proliferation index and microvessel density. Remarkably, the combination of zibotentan with both cisplatinum and paclitaxel was very effective in inhibiting tumor growth, neovascularization, and cell proliferation, representing a preclinical endpoint to guide combination therapy in clinical trials.

Combination Therapy with Novel Nanoparticle, SNS01-T, and Lenalidomide Triggers Synergistic Cytotoxicity in Vitro and in Vivo in Multiple Myeloma and Mantle Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4223-4223
Author(s):  
Catherine A Taylor ◽  
Terence Tang ◽  
Zhongda Liu ◽  
Sarah Francis ◽  
Zheng Qifa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combination Therapy ◽  
Tumor Growth ◽  
B Cell ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
Significant Activity ◽  
Rpmi 8226

Abstract Abstract 4223 SNS01-T is a novel nanoparticle that is designed to selectively initiate apoptosis in B-cell cancers such as multiple myeloma and B-cell lymphomas. SNS01-T is comprised of a plasmid encoding a pro-apoptotic form of the eukaryotic translation initiation factor 5A (eIF5A) containing a single-point mutation that prevents hypusination, an siRNA that inhibits expression of the pro-survival hypusine-eIF5A protein, and a polymer that serves to assemble the nucleic acids into a nanoparticle. SNS01-T is currently being investigated in a multi-site, open-label Phase1b/2a dose escalation study in subjects with relapsed or refractory multiple myeloma (MM). SNS01-T and its preclinical precursors have been studied extensively in multiple myeloma and B cell lymphoma tumor models. In this study we tested the in vitro and in vivo anti-cancer activity of SNS01-T in combination with the immunomodulatory drug lenalidomide. The combination of low doses of SNS01-T and lenalidomide synergistically reduced viability of RPMI 8226 MM cells and induced apoptosis to a greater degree than either drug alone. To determine whether SNS01-T treatment increases the anti-myeloma activity of lenalidomide in vivo, 0.375 mg/kg SNS01-T was combined with either 15 or 50 mg/kg lenalidomide in a RPMI 8226 xenograft model of multiple myeloma. Mice were dosed for two cycles of treatment for a total of 11 weeks of dosing. Mice with no measurable tumor at the end of the first cycle of treatment did not receive treatment in the second cycle but were monitored closely for tumor recurrence. A two-week observation period at the end of the study allowed monitoring of tumor growth after the cessation of the second cycle of treatment. At the end of the second cycle of dosing, tumor growth was inhibited by 84 % (p < 0.0001), 34 % (p = 0.05), and 98.1 % (p << 0.0001) in animals treated with SNS01-T, 50 mg/kg lenalidomide, and SNS01-T plus 50 mg/kg lenalidomide, respectively. Complete tumor regression (undetectable tumor) was achieved in 40% of mice treated with SNS01-T, 0% of mice treated with 50 mg/kg lenalidomide, and 83% of mice treated with the combination therapy of SNS01-T and 50 mg/kg lenalidomide. Complete regression of tumors treated with the combination therapy was maintained for more than 8 weeks without treatment until the end of the study in 4 of 6 (67%) of treated mice. Combining SNS01-T treatment with 50 mg/kg lenalidomide inhibited tumor growth more effectively than either drug alone and prolonged survival with 100% of mice surviving to the end of the 102-day study. Combination therapy with SNS01-T and 15 mg/kg lenalidomide also demonstrated significant activity in a murine JMV-2 mantle cell lymphoma (MCL) xenograft model. Treatment of mice with the drug combination of SNS01-T and lenalidomide resulted in a statistically significant increase in survival compared to either SNS01-T (p = 0.002; logrank test) or lenalidomide (p = 0.007) alone. Collectively, these preclinical studies indicate that the combination therapy of SNS01-T and lenalidomide is well tolerated, has significant activity against MM and MCL, and provides a strong rationale to evaluate SNS01-T and lenalidomide combination therapy to improve patient outcome in MM and B cell lymphomas. Disclosures: Taylor: Senesco Technologies Inc.: stock options Other. Dondero:Senesco Technologies Inc.: Employment. Thompson:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Enhanced antitumor effect of YM872 and AG1296 combination treatment on human glioblastoma xenograft models

2013 ◽  
Vol 118 (4) ◽  
pp. 838-845 ◽  
Author(s):  
Takashi Watanabe ◽  
Toshiyuki Ohtani ◽  
Masanori Aihara ◽  
Shogo Ishiuchi
Keyword(s):  
Cell Proliferation ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Xenograft Model ◽  
Glioblastoma Cells ◽  
Akt Phosphorylation ◽  
Combined Administration

Object Blockade of Ca++-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) inhibits the proliferation of human glioblastoma by inhibiting Akt phosphorylation, which is independent of the phosphatidylinositol 3-kinase pathway. Inhibiting platelet-derived growth factor receptor (PDGFR)–mediated phosphorylation causes growth inhibition in glioblastoma cells. The authors of this study investigated the effects of YM872 and AG1296, singly and in combination and targeting different pathways upstream of Akt, on Akt-mediated tumor growth in glioblastoma cells in vivo and in vitro. Methods The expression of AMPAR, PDGFR, and c-kit in glioblastoma cells was analyzed via immunofluorescence. Glioblastoma cells, both in culture and in xenografts grown in mice, were treated with YM872 and AG1296, singly or in combination. Inhibition of tumor growth was observed after treatment in the xenograft model. Cell proliferation assays were performed using anti–Ki 67 antibody in vivo and in vitro. The CD34-positive tumor vessel counts within the vascular hot spots of tumor specimens were evaluated. Phosphorylation of Akt was studied using Western blot analysis. Results Combined administration of YM872 and AG1296 had a significant enhanced effect on the inhibition of cell proliferation and reduction of tumor vascularity in the xenograft model. These agents singly and in combination demonstrated a significant reduction of Akt phosphorylation at Ser473 and inhibition of tumor proliferation in vitro, although combined administration had no enhanced antitumor effects. Conclusions The strongly enhanced antitumor effect of this combination therapy in vivo rather than in vitro may be attributable to disruption of the aberrant vascular niche. This combination therapy might provide substantial benefits to patients with glioblastoma.

Targeted Liposomal Paclitaxel Raises Tumor Vessel Leakiness

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P94-P94
Author(s):  
Sebastian Strieth ◽  
Martin E Eichhorn ◽  
Werner Alexander ◽  
Birgitta Sauer ◽  
Michael Teifel ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Human Cancer ◽  
Cationic Liposomes ◽  
Significant Inhibition ◽  
Cell Interactions ◽  
Vascular Targeting ◽  
Liposomal Paclitaxel

Problem Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG-1 therapy on tumor microvascular leakiness with respect to leukocyte-endothelial cell interactions, the targeting property of cationic liposomes and the therapeutic combination with conventional cisplatin chemotherapy. Methods Using dorsal skinfold chamber preparations in Syrian Golden hamsters in vivo fluorescence microscopy experiments were performed after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labelled albumin was measured to calculate microvessel permeability and intratumoral leukocyte-endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histological analysis. Results Microvascular permeability was significantly increased only after treatment with EndoTAG-1, while intratumoral leukocyte-endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments fluorescently-labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG-1 treatment and no signs of extravasation were observed. Subcutaneous A-Mel-3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG-1. Conclusion These data show that vascular targeting with EndoTAG-1 increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte-endothelial cell interactions. Manipulating the blood-tumor barrier by repeated tumor microvessel targeting using EndoTAG-1 can effectively be combined with tumor cell-directed conventional cisplatin chemotherapy. Significance Antivascular therapy using liposomal paclitaxel (EndoTAG-1) is currently undergoing Phase II clinical studies in human cancer patients. Referring to the present experimental data showing increased permeability of intratumoral microvessels combination therapy with conventional therapy appears to be a very promising strategy. Support This study was supported by grants of Munich Biotech AG, Neuried, Germany and by grants of the Novartis Foundation for Therapeutic Research, Nürnberg, Germany.

scholarly journals RBIO-02. COMBINING RADIOTHERAPY WITH PI3K ISOFORM-SPECIFIC INHIBITOR DECREASES RADIORESISTANCE AND SUPPRESSES TUMOR GROWTH IN GLIOBLASTOMA CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii192-ii192
Author(s):  
Mi Youn Seol ◽  
Hong In Yoon
Keyword(s):  
Side Effects ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Synergistic Effects ◽  
Specific Inhibitor ◽  
Akt Signaling ◽  
Growth Delay ◽  
Migration Ability ◽  
Dismal Prognosis

Abstract Glioblastoma (GBM) is the most malignant tumor that occurs within the brain and shows the dismal prognosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway plays a principal role in GBM. Also, Activated PI3K-AKT signaling by irradiation induces radioresistance. But, the pan-PI3K inhibitors cause side-effects in clinical trial. Different PI3K isoforms play non-redundant roles in brain tumor growth and regulating radioresistance. So it is expected that selective inhibition of PI3K isoforms decrease side effects. We demonstrated whether combining radiotherapy with the PI3K isoform inhibitor reduces radioresistance and tumor growth in GBM. Glioma261 expressed luciferase (GL261-luc) cell lines were used to investigate the synergistic effects of combining radiotherapy with the PI3K isoform inhibitors. GL261-luc were irradiated 1Gy with or without PI3K isoform inhibitors. GL261-luc irradiated by 1Gy was suppressed cell proliferation about 70% compared to control (p&lt; 0.001). When irradiated with PI3K-isform inhibitor, each growth rate was about 18% (PI3K-pan, p&lt; 0.00001), 25% (PI3K-alpha, p&lt; 0.00001), 30% (PI3K-delta, p&lt; 0.00001), 45% (PI3K-gamma/delta, p&lt; 0.00001). Significant increase of DNA DSB and decrease of the migration ability were shown by combination radiotherapy with PI3K- isoform inhibitor. Especially, combining radiotherapy, PI3K-alpha inhibitor showed the effect similar to PI3K-pan inhibitor (In vitro). So, we analyzed combination therapy effects using PI3K-alphs inhibitor and radiotherapy in vivo. We demonstrated that combining radiotherapy with the PI3K-alpha isoform inhibitor markedly delayed tumor growth than radiotherapy only (p&lt; 0.0001). Also, we confirmed that survival rate of intracranial GBM mouse was increased by combination therapy (p&lt; 0.01). In addition, the expression of PD1, regulator of cancer immune system, in spleenocyte was increased by combination therapy (p&lt; 0.001) (In vivo). Our results demonstrate that combining radiotherapy with the PI3K-alpha isoform improve radiosensitivity, which result in significant tumor growth delay and improved survival.

Anti-Heparanase Therapy in Combination with Conventional Chemotherapy Potently Inhibits Multiple Myeloma Growth in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5165-5165
Author(s):  
Joseph P. Ritchie ◽  
Annamaria Naggi ◽  
Giangiacomo Torri ◽  
Benito Casu ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Intracellular Signaling ◽  
Dependent Manner ◽  
Conventional Chemotherapy ◽  
In Vivo Models

Abstract Targeted agents directed at specific intracellular signaling pathways and the tumor microenvironment have improved the management of many cancers, including multiple myeloma. Work by our lab has demonstrated that heparanase, an endo-β-D-glucuronidase which cleaves the glycosidic bond of heparan sulfate chains at only a few sites, is expressed by a subpopulation of myeloma cells. Expression of heparanase promotes myeloma growth and spontaneous metastasis to bone, correlates with increased microvessel density and is an indicator of poor patient prognosis. This makes heparanase a viable target for myeloma therapy. Current approaches for treating multiple myeloma are ineffective, with relapse occurring frequently. Recently, a modified non-anticoagulant species of heparin, designated SST0001, was identified as a specific inhibitor of heparanase. SST0001, when tested in multiple in vivo models of myeloma, potently inhibited both angiogenesis and tumor growth in a dose dependent manner. However, in vitro, it did not have direct tumor cell cytotoxicity. Therefore, because SST0001 apparently targets the tumor microenvironment and conventional chemotherapy directly targets the tumor cell, we hypothesized that combination therapy would synergistically decrease tumor burden and provide an alternative biological approach to treating myeloma. In this study, using a syngeneic subcutaneous model of myeloma, we screened three potential novel combinations; SST0001 + dexamethasone, SST0001 + doxorubicin, and SST0001 + bortezomib. While all three combinations were effective in blocking tumor growth, SST0001 + dexamethasone was identified as being the most potent and was chosen for further testing. In two separate SCID-subcutaneous models using the CAG and MM1.R dexamethasone resistant human myeloma cell lines, SST0001 + dexamethasone also proved to be a potent inhibitor of tumor growth in vivo. These results identify an effective combination therapy, which is not cell line specific, for further development and translation into clinical trials.

The degree of inhibition of thyroid follicular cell proliferation by iodide is a highly individual characteristic of each cell and differs profoundly in vitro and in vivo

1994 ◽  
Vol 130 (6) ◽  
pp. 595-600 ◽  
Author(s):  
Simon Aeschimann ◽  
Hans Gerber ◽  
Christine von Grünigen ◽  
Madeleine Oestreicher ◽  
Hugo Studer
Keyword(s):  
Cell Proliferation ◽  
Three Dimensional ◽  
Inhibitory Effect ◽  
Individual Characteristic ◽  
Follicular Cell ◽  
Thyroid Follicular Cell ◽  
Inhibiting Effect ◽  
Growth Inhibiting

Aeschimann S, Gerber H, von Grünigen C, Oestreicher M, Studer H. The degree of inhibition of thyroid follicular cell proliferation by iodide is a highly individual characteristic of each cell and differs profoundly in vitro and in vivo. Eur J Endocrinol 1944;130:595–600. ISSN 0804–4643 Pharmacological concentrations of iodide (>1 × 10−6 mol/l) are known to inhibit thyroid follicular cell growth in vitro. However, the inhibitory effect varies widely, depending on experimental conditions, and usually does not exceed 50%. We demonstrate that iodide (10−4 mol/l) inhibits the growth of FRTL-5 cells in different passages by 11–67%. When five subclones of FRTL-5 cells were compared to the wild type, iodide-induced growth inhibition varied between 25% and 46%. The individual degree of inhibition of each clone was reproducible in two subsequent passages, suggesting that it is a stable constitutive trait. When FRTL-5 cells were grown first in three-dimensional clusters and then transplanted onto nude mice with high endogenous thyrotropin secretion, iodide at a serum concentration of less than 5.7 × 10−7 mol/l nearly completely blocked cell replication in the transplants but not in the mice's own thyroid. Five cell lines, prepared from autonomously growing hyperthyroid feline multinodular goiters, were nearly completely resistant to the growth-inhibitory effect of iodide. These observations suggest that the sensitivity towards the growth-inhibiting effect of iodide is a highly variable, stable trait of each thyrocyte, even in cloned cell populations. Some FRTL-5 cells and, even more so, cells prepared from autonomously growing nodular feline goiters are resistant constitutively to the growth-inhibiting effect of iodide. Three-dimensional clusters of FRTL-5 cells growing as transplants in recipient mice are growth-arrested totally by iodide concentrations more than 175 times lower than those partially inhibiting monolayer cultures, while growth of the intact thyroid of the recipient mouse remains unaffected or is even enhanced. Thus, the sensitivity of thyrocytes toward iodide is different fundamentally in vitro and in vivo. Hugo Studer, Medizinische Universitaetsklinik, Inselspital, CH-3010 Bern, Switzerland

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