Cytotoxic and cytocompatible comparison among seven photoinitiators-triggered polymers in different tissue cells.

Photoinitiators (PIs) are widely used for photopolymerization in industrial area and recently paid close attention to in biomedical field. However, there are few reports on their toxicity to human health. Here we explored cytotoxicity and cytocompatibilty of seven commercial and industrial-used PIs for developing their potential clinical application. Phenylbis(acyl) phosphine oxides (BAPO), 2-Benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone (369), 4,4'-Bis(diethylamino) benzophenone (EMK), Diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide (TPO), and 2-Isopropylthioxanthone (ITX) caused different extent cytotoxicities to four tissue types of cells at the concentrations of 1 to 50 µM under a non-irradiation condition, of which the BAPO cytotoxicity was the highest, whereas Ethyl (2,4,6-trimethylbenzoyl) phenylphosphinate (TPOL) and Methyl benzoylformate (MBF) displayed the lowest cellular toxicity. The cell lines and primary cells appeared highly sensitive to BAPO toxicity, the primary lymphocytes relatively to photoinitiator 369 (369) and EMK toxicities, LO2 cells to EMK and TPO toxicities, the primary lymphocytes and HUVEC-12 cells to MBF toxicity, but only HEK293T cells not to 369 toxicity. Furthermore, these PIs led to increasing cytotoxicity to different extents after exposure to 455 nm blue light, which is consistent with non-irradiation tendency. All the cells presented low sensitivity to TPOL and MBF, of which TPOL-triggered polymer is dramatically superior in its cytocompatibility to MBF, and in its transparency to clinically exclusively-used camphorquinone (CQ). The novel findings indicate that BAPO is the most toxic among the seven PIs, but TPOL and MBF are the least toxic, directing their development and application. Combined their triggered polymer cytocompatibility and color with reported deep curing efficiency, TPOL is more promising to be applied especially to clinical practice.

Cytotoxic effects of thioxanthone derivatives as photoinitiators on isolated rat hepatocytes.

Thioxanthone and its analogues, 2- or 4-isopropylthioxanthone, 2-chlorothioxanthone, 2,4-diethylthioxanthone (DETX) and xanthone, are used as photoinitiators of ultraviolet (UV) light-initiated curable inks. As these photoinitiators were found in numerous food/beverage products packaged in cartons printed with UV-cured inks, the cytotoxic effects and mechanisms of these compounds were studied in freshly isolated rat hepatocytes. The toxicity of DETX was greater than that of other compounds. DETX elicited not only concentration (0-2.0 mm)- and time (0-3 hours)-dependent cell death accompanied by the depletion of cellular adenosine triphosphate (ATP), and reduced glutathione (GSH) and protein thiol levels, but also the accumulation of GSH disulfide and malondialdehyde. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or N-acetyl-l-cysteine (NAC) at a concentration of 5.0 mm ameliorated DETX (1 mm)-induced cytotoxicity. Further, the exposure of hepatocytes to DETX resulted in the induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential, both of which were partially prevented by the addition of NAC. These results indicate that: (1) DETX-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were, at least in part, ameliorated by the addition of fructose; and (3) GSH loss and/or ROS formation was prevented by NAC. Taken collectively, these results suggest that the onset of toxic effects caused by DETX may be partially attributable to cellular energy stress as well as oxidative stress.

In silico prediction and in vivo analysis of antiestrogenic potential of 2-isopropylthioxanthone (2-ITX) in juvenile goldfish (Carassius auratus).

Previous studies have shown both anti-estrogenic and anti-androgenic activities of 2-isopropylthioxanthone (2-ITX), a well known food contaminant, in in vitro assays. However, no data are available on the anti-estrogenic potentials and risks of 2-ITX in aquatic organisms. This work evaluated the potential endocrine disrupting effects of 2-ITX at the level of estrogen receptor (ER) signaling cascade using juvenile goldfish (Carassius auratus) as model. Firstly, we investigated the ligand binding efficiency of 2-ITX to the ligand binding domains (LBD) of goldfish ER subtypes using a molecular docking approach. Secondly, we assessed the effects of 2-ITX on E2-induced hepatic expression of ERα1, ERß1, ERß2, and vitellogenin (VTG) in vivo. Crosstalk between ER-VTG and aryl hydrocarbon receptor 2 (AhR2)-cytochrome P4501A (CYP1A) was also investigated. Fish were injected with increasing doses of 2-ITX ranging from 2 to 10µg/g BW, and results were compared to the effect of tamoxifen, a well-known ER modulator. We observed that compared to ERß, the interaction potentials of 2-ITX to goldfish ERα1 LBD was more stable in the inactive receptor conformation. The in silico docking simulation analysis also revealed that 2-ITX acted as agonist for the goldfish AhR2 LBDs suggesting the ability of this compound to activate the cross-talk between the ERα- and AhR-signaling pathways. In vivo experiments confirm in silico simulation predictions demonstrating that 2-ITX reduced the estrogenicity of E2 at both transcriptional and post-transcriptional levels, indicating a clear anti-estrogenic effect. Co-exposure of E2 and 2-ITX also resulted in a significant decrease of CYP1A gene expression with respect to 2-ITX alone. Results from these studies collectively revealed that the antiestrogenic property of 2-ITX can be ascribed to a combination of effects on multiple signaling pathways suggesting the potential for this environmental contaminant to affect the hormonal control of reproductive processes in fish.

Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019.

We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K ("responder" genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the "responder" profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.

Endocrine-disrupting effects of thioxanthone photoinitiators.

Photoinitiators used in food packaging ink, such as 2-isopropylthioxanthone (2-ITX), have been shown to migrate into food and beverages. Recently, several studies indicated that 2-ITX might be an endocrine-disrupting chemical. In this work, the effects of 2-ITX, 4-isopropylthioxanthone (4-ITX), 2,4-diethylthio xanthone (2,4-diethyl-TX), 2-chlorothioxanthone (2-chloro-TX), and 1-chloro-4-propoxythioxanthone (1-chloro-4-propoxy-TX) on steroidogenesis and androgen and estrogen receptor-mediated transcription activation have been studied using human H295R adrenocarcinoma cells and yeast hormone bioassays, respectively. None of the compounds showed androgenic or estrogenic activities, but clear antiandrogenic and antiestrogenic activities were observed for 2-ITX, 4-ITX, and 2,4-diethyl-TX, whereas 2-chloro-TX showed only antiandrogenic activity. In an adapted version of the H295R steroidogenesis assay, using gas chromatography-tandem mass spectrometry analysis of H295R media, all five compounds increased levels of 17ß-estradiol and estrone. H295R cells incubated with 2-ITX also showed significantly reduced androgen and increased pregnenolone and progesterone levels. Expression of particular steroidogenic genes, including the one encoding for aromatase (CYP19A1), was significantly upregulated after incubation of H295R cells with 2-ITX, 4-ITX, and 2,4-diethyl-TX. In line with the increased CYP19A1 mRNA expression, 2-ITX increased catalytic activity of aromatase in H295R cells as measured by cognate aromatase assays. The results indicate that thioxanthone derivatives can act as potential endocrine disruptors both at the level of nuclear receptor signaling and steroid hormone production.

AhR-agonistic, anti-androgenic, and anti-estrogenic potencies of 2-isopropylthioxanthone (ITX) as determined by in vitro bioassays and gene expression profiling.

2-Isopropylthioxanthone (2-ITX) has been widely used as a photoinitiator in printing ink of packaging materials. A few years ago, this compound got special attention since it was detected in milk and fruit drinks. Since little is known about possible effects of this compound on human health, studies were initiated to investigate its properties, starting with in vitro studies. Structural similarities between ITX and the AhR-agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and furanocoumarins, prompted us to investigate whether ITX could have the potency to activate the AhR. ITX showed a clear response in the DR CALUX bioassay and also induced EROD activity in H4IIE rat hepatoma cells. Microarray studies in these cells showed a gene expression profile similar to that of TCDD. Moreover, using yeast-based estrogen and androgen bioassays, it was demonstrated that ITX, but not TCDD, has potential anti-estrogenic and anti-androgenic properties. The observed in vitro effects warrant further in vivo studies for confirmation and hazard characterization.

QTc monitoring during a phase I study: experience with SR271425.

OBJECTIVE: SR271425 is a thioxanthone cytotoxic drug that induces dose-related cardiac electrophysiologic changes in preclinical models. A phase I trial was conducted to determine the maximally tolerated dose and safety profile, notably cardiac events. METHODS: SR271425 was administered weekly as a 2-hour single intravenous infusion with a fixed 30 mg/m2 increment at each dose level (DL). A sustained cardiac evaluation was performed. ECG parameters were evaluated at bedside by an investigator or a cardiologist, as well as by central reading for dose limiting toxicity (DLT) determination. RESULTS: Sixteen patients were treated. Five DLs were explored, from 75 mg/m2/wk to 195 mg/m2/wk. Fourteen patients (87.5%) experienced noncardiac adverse events related to treatment; only 2 patients presented grade 3 toxicity (nausea/vomiting and GGT increase) and no grade 4 toxicities were reported. Asymptomatic grade 1 or 2 QTcF prolongations were observed in 5 patients during central readings, and in 4 cases at bedside. One QTc-DLT, registered at bedside (grade 2), was unconfirmed at central reading, while another QTc-DLT, not noted at bedside, was highlighted by central reading. No arrhythmias or QRS prolongations were observed. CONCLUSIONS: The maximum tolerated dose of SR271425 was not reached in this trial due to early termination of the trial, not related to cardiac toxicity, following the termination of the development program by the sponsor. Sustained ECG monitoring is quite feasible in oncology phase I trials, but discrepancies between bedside and central evaluation could lead to conflicting decisions for management of patient care.

Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice.

Historically, many new anticancer agents were first detected in a prescreen; usually consisting of a molecular/biochemical target or a cellular cytotoxicity assay. The agent then progressed to in vivo evaluation against transplanted human or mouse tumors. If the investigator had a large drug supply and ample resources, multiple tests were possible, with variations in tumor models, tumor and drug routes, dose-decrements, dose-schedules, number of groups, etc. However, in most large programs involving several hundred in vivo tests yearly, resource limitations and drug supply limitations have usually dictated a single trial. Under such restrictive conditions, we have implemented a flexible in vivo testing protocol. With this strategy, the tumor model is dictated by in vitro cellular sensitivity; drug route by water solubility (with water soluble agents injected intravenously); dosage decrement by drug supply, dose-schedule by toxicities encountered, etc. In this flexible design, many treatment parameters can be changed during the course of treatment (e.g., dose and schedule). The discovery of two active agents are presented (Cryptophycin-1, and Thioxanthone BCN 183577). Both were discovered by the intravenous route of administration. Both would have been missed if they were tested intraperitoneally, the usual drug route used in discovery protocols. It is also likely that they would have been missed with an easy to execute fixed protocol design, even if injected i.v.

Reactions with thiaxanthen-9-ol: new thiaxanthene derivatives with molluscicidal and nematocidal activity.

Thiaxanthen-9-ol (1) was condensed with nitriles 2a-e to yield the thiaxanthen-9-yl-acetonitriles 3a-e. With the thiols 7a-d, 1 yielded the thioethers 8a-d.

[Biochemical mechanisms of the hepatotoxicity of psychotropic drugs]. / Mécanismes biochimiques de l'hépatotoxicité des psychotropes.

The first part of this article presents the mechanisms for the hepatotoxicity of xenobiotics known to date, in particular the interference with the metabolism of bilirubin, hepatotoxicity arising from the metabolism of drugs as well as hepatotoxicity due to immunological factors. In the second part, the classification of the diverse hepatic diseases due to drugs is presented: acute injury (cytotoxic, cholestatic, mixed) and chronic damage. The extrahepatic manifestations of drug-induced hepatic injury are also mentioned. Finally, in the third part, we present the principal cases of hepatotoxicity caused by psychotropic drugs: antidepressants (MAOIs and tricyclics), neuroleptics (phenothiazines, thioxanthenes, butyrophenones and benzamides) and anxiolytics, to which we add the anticonvulsants (phenytoin, phenacemide, oxazolidinediones, carbamazepine and valproic acid). We describe the mechanism of hepatotoxicity when known and we attempt to present the type(s) of hepatic injury it causes.

Genetic analysis of adenine-3 mutants induced by hycanthone, lucanthone and their indazole analogs in Neurospora crassa.

Ad-3 mutants induced by hycanthone, lucanthone and their indazole analogs, IA-3, IA-4 and IA-5 were studied to characterize the genetic alterations produced by these agents in Neurospora crassa. The results of genetic analysis indicate that, in marked contrast to past experiments with chemical mutagens on heterokaryon 12, all of these antischistosomal agents induce a very high frequency of multilocus deletions.

Carcinogenic potential of hycanthone in mice and hamsters.

Hycanthone was administered to Schistosoma mansoni-infected and non-infected Syrian golden hamsters and Swiss mice by intraperitoneal and intramuscular injection of amounts up to the maximum tolerated dose. No tumors attributable to treatment were observed in hamsters. In infected mice, the overall incidence of hepatomas and hepatocellular carcinomas increased from 3.4% in untreated mice to 10.6% in those treated with hycanthone. Non-infected control mice developed 0.8% of these tumors compared to 10.2% in mice treated with hycanthone. Despite the use of high dose levels of hycanthone, statistical significance was attained only with non-infected female mice injected intraperitoneally and intramuscularly with hycanthone and then only at confidence levels of 92 and 95% respectively.

Absence of liver toxicity in 2723 patients treated with hycanthone in St. Lucia.

This report is submitted not to refute the occurrence of any toxicity but to record that in St. Lucia, given reasonable care in administration and careful follow-up, we have not yet encountered jaundice, liver necrosis or other serious side effects.

Absence of liver toxicity in 2723 patients treated with hycanthone in St. Lucia

This report is submitted not to refute the occurence of any toxicity but to record that in St. Lucia, given reasonable care in administration and careful follow-up, we have not yet encountered jaundice, liver necrosis or other serious side effects.(Summary)

The toxicity of thioxanthene neuroleptics to isolated rat liver cells.

A series of thioxanthenes was tested for cytotoxicity to isolated rat hepatocytes, as measured by the loss of an intracellular enzyme (GOT) to the surrounding medium. The relative order of potency was found to be: SKF 10812 greater than cis- = trans-chlorprothixene = N-756A greater than cis- = trans-flupenthixol greater than xanthiol greater than methixene = cis- = trans-clopenthixol = N-716 greater than N-710. The presence of an unsaturated exocyclic bond increased the apparent toxicity as did the presence of a substituent (trifluoromethyl, chlorine, bromine) at the two position of the tricyclic nucleus. The trifluoromethyl substituted thioxanthenes were three to four times more potent than their halogenated analogs, but there were no differences in potency among the halogenated (chlorine or bromine) thioxanthenes. Compounds which had a dimethylaminopropylidene side chain were five to six times stronger in causing enzyme leakage than were their analog which had a hydroxyethylpiperazinylpropylidene side chain. Although only the cis-isomers of each compound are highly active neuroleptics, both isomers were equipotent at causing the efflux of GOT from rat hepatocytes.

Hycanthone analogs: dissociation of mutagenic effects from antischistosomal effects.

N-Oxidation at the diethylamino group of hycanthone, of lucanthone, and of two chlorobenzothiopyranoindazoles resulted in a marked reduction in mutagenic activity, while antischistosomal activity was retained or even enhanced. Introduction of chlorine into the 8-position of benzothiopyranoindazoles reduced acute toxicity but had no effect on chemnotherapeutic potency. These dissociations of biological activities indicate that safer antischistosomal compounds of this class can be developed.