scholarly journals Role of Short- and Long-Lived Reactive Species on the Selectivity and Anti-Cancer Action of Plasma Treatment In Vitro

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 615
Author(s):  
Kyriakos Sklias ◽  
João Santos Sousa ◽  
Pierre-Marie Girard
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Phase I ◽  
Plasma Treatment ◽  
Tumor Cells ◽  
Phase Ii ◽  
Treatment Modalities ◽  
Normal Cells ◽  
Anti Cancer

(1) Plasma-activated liquids (PAL) have been extensively studied for their anti-cancer properties. Two treatment modalities can be applied to the cells, direct and indirect plasma treatments, which differ by the environment to which the cells are exposed. For direct plasma treatment, the cells covered by a liquid are present during the plasma treatment time (phase I, plasma ON) and the incubation time (phase II, plasma OFF), while for indirect plasma treatment, phase I is cell-free and cells are only exposed to PAL during phase II. The scope of this work was to study these two treatment modalities to bring new insights into the potential use of PAL for cancer treatment. (2) We used two models of head and neck cancer cells, CAL27 and FaDu, and three models of normal cells (1Br3, NHK, and RPE-hTERT). PBS was used as the liquid of interest, and the concentration of plasma-induced H2O2, NO2− and NO3−, as well as pH change, were measured. Cells were exposed to direct plasma treatment, indirect plasma treatment or reconstituted buffer (PBS adjusted with plasma-induced concentrations of H2O2, NO2−, NO3− and pH). Metabolic cell activity, cell viability, lipid peroxidation, intracellular ROS production and caspase 3/7 induction were quantified. (3) If we showed that direct plasma treatment is slightly more efficient than indirect plasma treatment and reconstituted buffer at inducing lipid peroxidation, intracellular increase of ROS and cancer cell death in tumor cells, our data also revealed that reconstituted buffer is equivalent to indirect plasma treatment. In contrast, normal cells are quite insensitive to these two last treatment modalities. However, they are extremely sensitive to direct plasma treatment. Indeed, we found that phase I and phase II act in synergy to trigger cell death in normal cells and are additive concerning tumor cell death. Our data also highlight the presence in plasma-treated PBS of yet unidentified short-lived reactive species that contribute to cell death. (4) In this study, we provide strong evidence that, in vitro, the concentration of RONS (H2O2, NO2− and NO3−) in combination with the acidic pH are the main drivers of plasma-induced PBS toxicity in tumor cells but not in normal cells, which makes ad hoc reconstituted solutions powerful anti-tumor treatments. In marked contrast, direct plasma treatment is deleterious for normal cells in vitro and should be avoided. Based on our results, we discuss the limitations to the use of PAL for cancer treatments.

ZIO-101 (S-dimethylarsino-glutathione): Phase I/II trials in advanced/progressive multiple myeloma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8109-8109 ◽  
Author(s):  
J. R. Berenson ◽  
S. Jaganath ◽  
D. Reece ◽  
R. Boccia ◽  
R. Soebel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Maximum Tolerated Dose ◽  
Oxygen Species ◽  
Low Concentrations ◽  
Anti Cancer ◽  
Organic Arsenic ◽  
Grade 3 ◽  
Dose Limiting Toxicity

8109 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD > 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues. No significant financial relationships to disclose.

scholarly journals Inhibitory Effects of a Reengineered Anthrax Toxin on Canine Oral Mucosal Melanomas

Toxins ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 157 ◽  
Author(s):  
Adriana Tomoko Nishiya ◽  
Marcia Kazumi Nagamine ◽  
Ivone Izabel Mackowiak da Fonseca ◽  
Andrea Caringi Miraldo ◽  
Nayra Villar Scattone ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Evaluation Criteria ◽  
Anthrax Toxin ◽  
Treatment Modalities ◽  
Inhibitory Effects ◽  
Upa Receptor ◽  
New Treatment ◽  
Oral Malignancy

Canine oral mucosal melanomas (OMM) are the most common oral malignancy in dogs and few treatments are available. Thus, new treatment modalities are needed for this disease. Bacillus anthracis (anthrax) toxin has been reengineered to target tumor cells that express urokinase plasminogen activator (uPA) and metalloproteinases (MMP-2), and has shown antineoplastic effects both, in vitro and in vivo. This study aimed to evaluate the effects of a reengineered anthrax toxin on canine OMM. Five dogs bearing OMM without lung metastasis were included in the clinical study. Tumor tissue was analyzed by immunohistochemistry for expression of uPA, uPA receptor, MMP-2, MT1-MMP and TIMP-2. Animals received either three or six intratumoral injections of the reengineered anthrax toxin prior to surgical tumor excision. OMM samples from the five dogs were positive for all antibodies. After intratumoral treatment, all dogs showed stable disease according to the canine Response Evaluation Criteria in Solid Tumors (cRECIST), and tumors had decreased bleeding. Histopathology has shown necrosis of tumor cells and blood vessel walls after treatment. No significant systemic side effects were noted. In conclusion, the reengineered anthrax toxin exerted inhibitory effects when administered intratumorally, and systemic administration of this toxin is a promising therapy for canine OMM.

Role of Phase II Enzymes in the Bioactivation of 1,4-Dichlorobenzene and 1,4-Dibromobenzene

1996 ◽  
Vol 24 (4) ◽  
pp. 603-608
Author(s):  
Moreno Paolini ◽  
Laura Pozzetti ◽  
Renata Mesirca ◽  
Andrea Sapone ◽  
Paola Silingardi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Phase I ◽  
Phase Ii ◽  
Covalent Binding ◽  
Fold Increase ◽  
Test System ◽  
Oxidative Enzymes ◽  
Transferase Activity ◽  
Genetic Toxicology

The use of sodium phenobarbital (PB, CYP2B1 inducer) combined with β-naphthoflavone (β-NF, 1A1) to induce certain Phase I reactions in S9 liver fractions is a standard method for conducting short-term bioassays for genotoxicity. However, because post-oxidative enzymes are also able to activate many precarcinogens, we tested the possibility of adapting S9 liver fractions derived from Phase II-induced rodents to the field of genetic toxicology. In this study, S9 liver fractions derived from Swiss albino CD1 mice fed 7.5g/kg 2-(3)-tert-butyl-4-hydroxyanisole (BHA; a monofunctional Phase II-inducer) for 3 weeks, show a clear pattern of induction with an approximately 3.5–9.5-fold increase in glutathione S-transferase activity. In vitro DNA binding of the promutagenic agents, [14C]-l,4-dichlorobenzene (DCB) and [14C]-1,4-dibromobenzene (DBB), is mediated by such metabolic liver preparations and showed a significant increase in covalent binding capability. In some instances, enzyme activity was more elevated when compared to that obtained with traditional (Phase I-induced) S9. Together with DNA binding, the genetic response of these chemicals in the diploid D7 strain of Saccharomyces cerevisiae used as a biological test system, revealed the ability of the BHA-derived preparations to activate the promutagenic agents, as exemplified by the significant enhancement of mitotic gene-conversion (up to 5.2-fold for DCB and 3.4-fold for DBB) and reverse point mutation (up to 3.6-fold for DCB and 2.5-fold for DBB) at a 4mM concentration. This novel metabolising biosystem, with enhanced Phase II activity, is recommended together with a traditional S9, for detecting unknown promutagens in genotoxicity studies. The routine use of either oxidative or post-oxidative S9 increases the responsiveness of the test and can contribute to the identification of promutagens not detected when using traditional protocols.

Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

2005 ◽  
Vol 23 (7) ◽  
pp. 1555-1563 ◽  
Author(s):  
Susan M. Blaney ◽  
Frank M. Balis ◽  
Stacey Berg ◽  
Carola A.S. Arndt ◽  
Richard Heideman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Neoplastic Meningitis ◽  
In Vitro Cytotoxicity ◽  
Pharmacokinetic Studies ◽  
Preclinical Studies ◽  
Phase Ii Trials ◽  
Cytotoxicity Studies

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Biocatalytic synthesis of terpene esters and their biological activity in human glioma cells

2021 ◽  
Vol 22 ◽  
Author(s):  
Mateusz Kutyła ◽  
Aleksandra Maciejczyk ◽  
Mariusz Trytek ◽  
Joanna Jakubowicz-Gil
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Fold Increase ◽  
Point Of View ◽  
Terpene Alcohols ◽  
Human Glioblastoma Multiforme ◽  
Anti Cancer ◽  
Therapeutic Molecules ◽  
Resistance To Chemotherapy

Background: Gliomas are highly malignant brain tumors with high resistance to chemotherapy. Therefore, investigations of new therapeutic molecules with high anti-glioma activity are of great importance. Objective: In this work, biocatalytic esterification of terpene alcohols with proven anti-cancer activity was performed to enhance their potency to induce cell death in human glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cell lines in vitro. Method and Results: We used primary terpene alcohols and carboxylic acids with a length of two to nine carbon atoms. The structure of the drinks influenced the esterification efficiency, which decreased in the following order: monocyclic > linear > bicyclic. Terpene alcohols and their esters only induced apoptotic cell death, which is highly desirable from a therapeutic point of view but did not induce autophagy and necrosis. The esterification of perillyl alcohol with butyric acid caused a 4-fold increase in cell death induction in the T98G line. Citronellol valerate, caprylate, and pelargonate and myrtenol butyrate, caprylate, and pelargonate also showed higher activity than their alcohol precursors. Conclusion: We have herein shown that esterification of natural alcohols by biocatalysis can improve the activity for other compounds investigated for their anti-glioma activity.

Effects of Ofloxacin Administration on the Reliability of Urine Glucose Testing

1996 ◽  
Vol 30 (5) ◽  
pp. 469-472
Author(s):  
Tsong-Mei Tsai ◽  
Brian F Shea ◽  
Paul F Souney ◽  
Fred G Volinsky ◽  
Joseph M Scavone ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Tertiary Care ◽  
Urine Samples ◽  
Care Hospital ◽  
Open Label ◽  
Urine Glucose ◽  
Glucose Testing

OBJECTIVE: TO study the effects of ofloxacin on the reliability of urine glucose testing. DESIGN: Open-label, nonrandomized. SETTING: A university-affiliated tertiary care hospital, ambulatory clinic. PARTICIPANTS: Ten healthy volunteers (8 men and 2 women) aged 22-39 years. MAIN OUTCOME MEASURES: Phase I (in vitro) involved the addition of selected amounts of ofloxacin to a set of standard 50-mL urine samples prepared to simulate glycosuria. Phase II (in vivo) involved the oral administration of ofloxacin 400 mg to 10 subjects. Urine was collected: (1) immediately predose, (2) pooled 0–4 hours postdose, and (3) pooled 4–8 hours postdose. Known glucose concentrations were then added to these samples. Clinitest and Diastix tests were performed on all samples. The accuracy of these tests in determining glucose concentrations was compared among urine samples taken before and after ofloxacin dosing. RESULTS: None of the ofloxacin concentrations in phase I (0,25,50, 100, 200,400, and 800 μg/mL) influenced these testing methods at the urine glucose concentrations of 0.0%, 0.5%, 1%, and 2%. Likewise, the accuracy of these two tests was unaffected by ofloxacin administration in phase II. CONCLUSIONS: In single-dose administration, ofloxacin does not interfere with Clinitest or Diastix for determining urine glucose concentrations. Supported by a grant from the RW Johnson Pharmaceutical Research Institute. Presented in abstract form at the American College of Clinical Pharmacy 1994 Winter Practice and Research Forum, February 6–9, 1994, San Diego. CA.

scholarly journals Tumor cell death visualization of renal cell carcinoma under the combined effect of the Gratiola officinalis extract and cyclophosphamide using fluorescent staining methods

2021 ◽  
pp. 2142004
Author(s):  
Artyom Mylnikov ◽  
Nikita Navolokin ◽  
Dmitry Mudrak ◽  
Natalya Polukonova ◽  
Alla Bucharskaya ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Human Kidney ◽  
Combined Effect ◽  
Tumor Cell Death ◽  
Staining Methods ◽  
Apoptotic Activity ◽  
Apoptosis And Necrosis ◽  
Number Of Cells

Objective of the study: We used fluorescence imaging methods of apoptosis and necrosis in human renal carcinoma A498 tumor cells in vitro to reveal the indicated forms of cell death under the combined effect of flavonoid-containing extract of Gratiola officinalis and cytostatic (cyclophosphamide). Materials and methods: The dyes were propidium iodide and acridine orange, which were used in the “alive and dead” test. This test helped us to identify the total number of dead cells in the forms of necrosis and apoptosis and the number of cells in which apoptosis had started, it was characterized by the appearance of apoptotic bodies or nucleus pyknosis. Results: We found the most pronounced cytotoxic activity at the ratio of extract of Gratiola officinalis and cyclophosphamide concentrations of 1:1. The number of living cells decreased when exposed to the ratio of extract and cytostatic concentrations of 2:1. When the ratio of concentration of the extract relative to the cytostatic increased to 3:1, the cytostatic activity of the extract began to appear, the total number of tumor cells decreased. The number of cells with nucleus pyknosis and the number of cells with apoptosis signs significantly increased at a 3:1 ratio of extract and cytostatic concentrations, which confirms the presence of pro-apoptotic activity of the studied combination. This trend indicates the dependence of a certain form of cell death (apoptosis, necrosis) on the ratio of extract and cytostatic doses, and it also demonstrates the cytostatic and cytotoxic effects of this combination. Conclusion: Fluorescence methods of investigation in the “alive and dead” test allowed us to visualize the forms of cell death of human kidney carcinoma A498 by combined exposure to the flavonoid-containing extract of Gratiola officinalis and cytostatic (cyclophosphamide) 24 h after exposure. We found that the combination with a concentration ratio of the extract and cyclophosphamide of 3:1 has the greatest effectiveness due to stimulation of the cytostatic effect and cytotoxic effect.

scholarly journals Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model

2020 ◽  
Vol 21 (11) ◽  
pp. 3998 ◽  
Author(s):  
Madalena Cipriano ◽  
Pedro F Pinheiro ◽  
Catarina O Sequeira ◽  
Joana S Rodrigues ◽  
Nuno G Oliveira ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
3D Model ◽  
Toxicological Assessment ◽  
Biotransformation Enzymes ◽  
Net Flux ◽  
Hepatotoxic Drug ◽  
Phase I And Ii ◽  
3D Spheroids

The need for competent in vitro liver models for toxicological assessment persists. The differentiation of stem cells into hepatocyte-like cells (HLC) has been adopted due to its human origin and availability. Our aim was to study the usefulness of an in vitro 3D model of mesenchymal stem cell-derived HLCs. 3D spheroids (3D-HLC) or monolayer (2D-HLC) cultures of HLCs were treated with the hepatotoxic drug nevirapine (NVP) for 3 and 10 days followed by analyses of Phase I and II metabolites, biotransformation enzymes and drug transporters involved in NVP disposition. To ascertain the toxic effects of NVP and its major metabolites, the changes in the glutathione net flux were also investigated. Phase I enzymes were induced in both systems yielding all known correspondent NVP metabolites. However, 3D-HLCs showed higher biocompetence in producing Phase II NVP metabolites and upregulating Phase II enzymes and MRP7. Accordingly, NVP-exposure led to decreased glutathione availability and alterations in the intracellular dynamics disfavoring free reduced glutathione and glutathionylated protein pools. Overall, these results demonstrate the adequacy of the 3D-HLC model for studying the bioactivation/metabolism of NVP representing a further step to unveil toxicity mechanisms associated with glutathione net flux changes.

scholarly journals In Vitro Anticancer Properties of Copper Metallodendrimers

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 155 ◽  
Author(s):  
Hołota ◽  
Magiera ◽  
Michlewska ◽  
Kubczak ◽  
del Olmo ◽  
...  
Keyword(s):  
Fluorescence Anisotropy ◽  
Drug Carriers ◽  
Haemolytic Activity ◽  
Surface Groups ◽  
Biological Processes ◽  
Normal Cells ◽  
Anticancer Properties ◽  
Transmission Electron ◽  
Anti Cancer

Newly synthesized carbosilane copper dendrimers (CCD) with chloride and nitrate surface groups seem to be good candidates to be used as gene and drug carriers in anti-cancer therapy, due to their properties such as size and surface charge. Copper attached to the nanoparticles is an important element of many biological processes and recently their anti-cancer properties have been widely examined. Zeta size and potential, transmission electron microscopy (TEM), circular dichroism (CD), analysis of haemolytic activity, and fluorescence anisotropy techniques were used to characterize copper dendrimers. Additionally, their cytotoxic properties toward normal (PBMC) and cancer (1301; HL-60) cells were examined. All tested dendrimers were more cytotoxic against cancer cells in comparison with normal cells.

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