Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

(1) Background: Melanoma is an aggressive neoplasm derived from melanocyte precursors with a high metastatic potential. Responses to chemotherapy and immunotherapy for melanoma remain weak, underlining the urgent need to develop new therapeutic strategies for the treatment of melanoma. (2) Methods: The viability of NHDF and A375 cell cultures after the administration of the tested isoxazole derivatives was assessed after 24-h and 48-h incubation periods with the test compounds in the MTT test. ROS and NO scavenging analyses, a glycoprotein-P activity analysis, a migration assay, a test of apoptosis, and a multiple-criteria decision analysis were also performed. (3) Results: All compounds that were tested resulted in a slower migration of melanoma neoplastic cells. The mechanism of the antitumor activity of the tested compounds was confirmed—i.e., the pro-apoptotic activity of the compounds in A375 cell cultures. Compound O7K qualified for further research. (4) Conclusions: All the tested compounds inhibited the formation of melanoma metastases and demonstrated the ability to reduce the risk of developing drug resistance in the tumor. The MCDA results showed that O7K showed the strongest antitumor activity.

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Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth in vitro

Oncology Letters ◽

10.3892/ol.2020.12002 ◽

2020 ◽

Vol 20 (5) ◽

pp. 1-1

Author(s):

Ilaria Lampronti ◽

Daniele Simoni ◽

Riccardo Rondanin ◽

Riccardo Baruchello ◽

Chiara Scapoli ◽

...

Keyword(s):

Cell Growth ◽

Tumor Cell ◽

Inhibitory Activity ◽

Tumor Cell Growth ◽

Apoptotic Activity ◽

Isoxazole Derivatives

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Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

RSC Advances ◽

10.1039/c6ra23940d ◽

2016 ◽

Vol 6 (106) ◽

pp. 104763-104781 ◽

Cited By ~ 13

Author(s):

Aleksandra Božić ◽

Aleksandar Marinković ◽

Snežana Bjelogrlić ◽

Tamara R. Todorović ◽

Ilija N. Cvijetić ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Antitumor Activity ◽

Cancer Stem Cell ◽

Cell Models ◽

Target Profile ◽

Apoptotic Activity ◽

2D And 3D ◽

Stem Cell Models

Study of antitumor activity of mono- and bis-quinoline based (thio)carbohydrazones on THP-1 and AsPC-1 cancer stem cells, revealed that thiocarbohydrazones had superior pro-apoptotic activity than carbohydrazones with multi-target profile activities.

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Antitumor efficacy and pharmacokinetics of a novel gemcitabine oral formulation (INNO-D07001) in xenograft animal models.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14699 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14699-e14699

Author(s):

CS Hsu ◽

W-H Hao ◽

J-J Wang ◽

T-H Lin ◽

R-Y Kuo

Keyword(s):

Antitumor Activity ◽

Oral Administration ◽

Tumor Growth ◽

Pancreatic Tumor ◽

Safety Information ◽

Oral Formulation ◽

Preclinical Study ◽

Significant Inhibition ◽

Pancreatic Tumors ◽

Total Body

e14699 Background: INNO-D07001 is a novel oral gemcitabine formulation which was developed to enhance the oral bioavailability of gemcitabine and it has been successfully demonstrated in both beagle dogs as well as nude mice. The objectives of this study were to examine the antitumor activity of this novel gemcitabine oral formulation in human xenograft models of pancreatic tumors with different daily doses as well as various dosing schedules. Methods: The INNO-D07001 dosing solutions (gemcitabine oral formulation) were formulated freshly before treatment and water for injection (USP) was used as the diluent. There were seven groups in the study and it was ten female NCr-nu/nu mice (with human CFPAC-1 pancreatic tumor) per group. Two doses (5 mg/kg and 10 mg/kg) and three dosing schedules (Q1D, Q2D, and Q3D) were examined. Water for injection (by oral administration) was used as the blank control and Gemzar (180 mg/kg by I.V.) was used as the active control. All INNO-D07001 dosing solutions were administered to mice by P.O. and, on the other hand, Gemzar was administered to mice by I.V. All animals were designed to receive doses for 12 days based on different doses and dosing schedules. Total body weights and tumor sizes were recorded continuously for evaluating the toxicity and antitumor activity, respectively, of INNO-D07001. Results: Oral administration of INNO-D07001 once daily at doses of 10 and 5 mg/kg/dose was not tolerated. In contrast, oral administration of INNO-D07001 on a Q2Dx6 schedule at a dose of 10 mg/kg/dose and on a Q3Dx4 schedule at doses of 10 and 5 mg/kg/dose was well tolerated. Moreover, the INNO-D07001 treatment at a dose of 10 mg/kg/dose on a Q2Dx6 schedule produced statistically significant inhibition of tumor growth (i.e. more than 60% inhibition rate comparing to the blank control) on the last treatment day. Conclusions: The novel gemcitabine oral formulation (INNO-D07001) is well tolerated and effective at a dose of 10 mg/kg/dose on a Q2Dx6 schedule to show the significant inhibition of pancreatic tumor growth. Future preclinical study in toxicity evaluation with repeating doses is ongoing in order to provide adequate safety information before entering phase I clinical study.

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PRECLINICAL STUDY OF ANTITUMOR ACTIVITY OF INDOLOCARBAZOLES N-GLYCOSIDES DERIVATIVE LCS-1208. REPORT II

Russian Journal of Biotherapy ◽

10.17650/1726-9784-2015-14-3-41-48 ◽

2015 ◽

Vol 14 (3) ◽

pp. 41-48 ◽

Cited By ~ 2

Author(s):

M. P. Kiseleva ◽

Z. S. Shprakh ◽

L. M. Borisova ◽

I. Yu. Kubasova ◽

L. G. Dezhenkova ◽

...

Keyword(s):

Antitumor Activity ◽

Preclinical Study

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ANTITUMOR ACTIVITY OF ANTI-INTEGRIN PROTEIN SAV-RGD ON XENOGRAFTED HUMAN SKIN MELANOMA WITH INTEGRIN AVG3 EXPRESSION

Problems in oncology ◽

10.37469/0507-3758-2019-65-3-458-462 ◽

2019 ◽

Vol 65 (3) ◽

pp. 458-462

Author(s):

Yelena Treshchalina ◽

Natalya Andronova ◽

Galina Smirnova ◽

Yelena Sholokhova ◽

Nikolay Tupitsyn ◽

...

Keyword(s):

Antitumor Activity ◽

Human Skin ◽

Anticancer Agents ◽

Combined Therapy ◽

Preclinical Study ◽

Amelanotic Melanoma ◽

Receptor Expression ◽

Skin Melanoma

Anti-integrins are considered as potential anticancer agents capable of inhibiting differentiation and proliferation of various malignant cells, including disseminated melanoma. The possibility of including anti-integrins with different RGD-motives in combined therapy schedules is discussed. We have studied the oridinal recombinant lyophilized protein SAV-RGD (lyo-SAV-RGD), specifically binding to melanoma cells by means of the Tripeptide Arg-Gly-Asp. As models of melanoma of the skin selected amalonaticus MeWo/mel- and pigmented melCher/mel+ with prospectively certain expression of the marker, giving subcutaneous xenograft in mice Balb/c nude. Objective: to evaluate the antitumor activity of lyo-SAV-RGD in vivo on human skin melanoma models melCher and MeWo with different melanogenesis ability and integrin avB3 expression. Both melanomas in vitro were shown to express integrin avB3 detected in melCher/mel+ cells with fluorescent-labeled rat antibodies Luc.H11 according to the expression component integrins avp3, p3-chain (CD61), and MeWo cells/mel- antibodies 23С6. In a high therapeutic total dose of 900 mg/kg, lyo-SAV-RGD inhibited growth of both melanomas in vivo with satisfactory tolerability. Compared to melCher/mel+, MeWo/mel-: T/Cmin=30% (p<0.05) versus T/ Cmin=50% (p=0.001) was more sensitive to treatment. The effect on melCher/mel+ was obtained only in the exponential phase of tumor growth. The results obtained allow us to consider it expedient to conduct an in-depth preclinical study of anti-integrin SAV-RGD, focused on the most aggressive disseminated amelanotic melanoma of the skin, regardless of the nature of blocking receptor expression.

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Strong Antitumor Activity of Bevacizumab and Aflibercept in Neuroendocrine Carcinomas: In-Depth Preclinical Study

Neuroendocrinology ◽

10.1159/000500591 ◽

2019 ◽

Vol 110 (1-2) ◽

pp. 50-62 ◽

Cited By ~ 1

Author(s):

María Rodríguez-Remírez ◽

Laura del Puerto-Nevado ◽

María Jesús Fernández Aceñero ◽

Hakimeh Ebrahimi-Nik ◽

Marlid Cruz-Ramos ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Therapeutic Option ◽

Human Cell Line ◽

Preclinical Study ◽

Tumor Control ◽

Tumor Growth Inhibition ◽

Bevacizumab Treatment ◽

Strong Antitumor Activity

Background: Neuroendocrine carcinoma (NEC) is a rare and very aggressive tumor. It has been greatly understudied, and very little is known about optimal treatment strategy for patients with this disease. The purpose of this study was to evaluate in vivo whether anti-vascular endothelial growth factor (VEGF) drugs could be a therapeutic alternative for these tumors with a poor prognosis. Methods: We have developed 2 xenograft models using either human cell line derived from lung (H460) or from colon (COLO320) NEC to assess the effect of 2 antiangiogenic drugs, aflibercept and bevacizumab, on tumor growth and their pathological characteristics. Additionally, tumors were subjected to immunohistochemistry staining and proteins were measured with Western blot and ELISA. Results: Both aflibercept and bevacizumab showed significant antitumor activity (p < 0.001). In the H460 model, aflibercept resulted in 94% tumor growth inhibition (TGI) and bevacizumab treatment resulted in 72.2% TGI. Similarly, in the COLO320 model, aflibercept and bevacizumab resulted in 89.3 and 84% TGI, respectively. Moreover, antitumor activity occurs early after treatment initiation. Using Tumor Control Index score, which address the kinetics of tumor growth in a way comparable to the methods used in human clinical studies, we confirmed that both drugs inhibit significantly tumor growth. When tumor stabilization was evaluated, aflibercept shows higher ability to stabilize NEC tumors than bevacizumab. Conclusion: Results derived from this study strongly support anti-VEGF therapies, especially aflibercept, as a novel therapeutic option in NECs. Further studies are necessary, but our observations encourage the evaluation of antiangiogenics in clinical trials combined with standard chemotherapy.

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Establishment and genetic characterization of cell lines derived from proliferating nasal polyps and sinonasal inverted papillomas

Scientific Reports ◽

10.1038/s41598-021-96444-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Thawaree Nukpook ◽

Tipaya Ekalaksananan ◽

Tohru Kiyono ◽

Pornthep Kasemsiri ◽

Watchareporn Teeramatwanich ◽

...

Keyword(s):

Cell Lines ◽

Cell Cultures ◽

Nasal Polyps ◽

Tandem Repeats ◽

Preclinical Study ◽

In Vitro Models ◽

Primary Cells ◽

Immortalized Cells ◽

Inverted Papillomas

AbstractTo better understand the pathogenesis of nasal polyps (NPs) and sinonasal inverted papillomas (SIPs), we aimed to establish cell lines from fresh tissues of NPs and SIPs and characterize them. Primary cell cultures were obtained from two NP tissues (NP2 and NP3) and one SIP tissue (IP4). All the cells were polygonal in shape, expressed cytokeratin 14, and had normal diploid chromosome status. HPV58 DNA was detected in NP3. To obtain immortal primary cells, NP2 and IP4 cells were transduced with a combination of mutant CDK4, cyclinD1 and TERT. These cells were thereafter named NP2/K4DT and IP4/K4DT, respectively. HPV58-positive NP3 cells were transduced with TERT alone, the resulting cells named NP3/T. Phenotypic and genotypic identity of original tissues and derived cells was investigated. All the cell cultures with transgenes were confirmed to be derived from their parental cells and primary tumor tissues by analysis of short tandem repeats (STR) and maintained in vitro growth, genetic profiles and gene expression characteristics of the primary cells. These virtually immortalized cells, as well as the primary cells, have potential as in vitro models for studying the pathogenesis of NPs and SIPs and for preclinical study to develop new therapeutic agents.

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Drug discovery targeting the mTOR pathway

Clinical Science ◽

10.1042/cs20171158 ◽

2018 ◽

Vol 132 (5) ◽

pp. 543-568 ◽

Cited By ~ 35

Author(s):

Alberto M. Martelli ◽

Francesca Buontempo ◽

James A. McCubrey

Keyword(s):

Antitumor Activity ◽

Human Cancer ◽

Mtor Inhibitors ◽

Metastatic Potential ◽

Current Status ◽

Oncogenic Signaling ◽

Metabolic Transformation ◽

Preclinical And Clinical Studies ◽

Mtor Complex 1

Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity in vitro. Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure.

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Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Journal of Skin Cancer ◽

10.1155/2013/828329 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

M. Klein ◽

M. Lotem ◽

T. Peretz ◽

S. T. Zwas ◽

S. Mizrachi ◽

...

Keyword(s):

Antitumor Activity ◽

Metastatic Melanoma ◽

Median Overall Survival ◽

Stage Iiic ◽

Safety And Efficacy ◽

Phase Ib ◽

Melanoma Metastases ◽

Disease Stabilization ◽

The Mean ◽

Unlabeled Antibody

There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of188Re-6D2 was escalated to 54 mCi. SPECT/CT revealed188Re-6D2 uptake in melanoma metastases. The mean effective half-life of188Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

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