Temozolomide-induced liver damage

Background

Temozolomide (TMZ) is an alkylating agent used in chemoradiotherapy and adjuvant chemotherapy regimens for treatment of newly diagnosed or recurrent glioblastoma. In Germany alone, 900,000 daily doses of the drug are prescribed each year. Therefore, all severe side effects of TMZ, even those rarely observed, are relevant to radiotherapists.

Materials and methods

We report a case of severe drug-induced toxic hepatitis that developed during chemoradiotherapy with TMZ in a patient with glioblastoma multiforme.

Results

Transaminase elevation was observed after 5 weeks of TMZ treatment, followed by severe jaundice symptoms which only subsided 2 months later. These findings were consistent with diagnosis of the mixed hepatic/cholestatic type of drug-induced toxic hepatitis. Due to the early termination of treatment, no life-threatening complications occurred in our patient. However, rare reports of encephalopathy and fatality as complications of TMZ therapy can be found in the literature.

Conclusion

When using TMZ for treatment of glioblastoma, monitoring of liver enzyme levels should be performed twice weekly to prevent fatal toxic hepatitis. In the case of any drug-induced hepatitis, TMZ must be discontinued immediately.

Zusammenfassung

Temozolomid (TMZ) ist als Alkylanz Bestandteil der Radiochemotherapie und der adjuvanten Chemotherapie zur Behandlung neu diagnostizierter und rezidivierender Glioblastome. Allein in Deutschland werden jährlich 90.000 Tagesdosen verordnet. Daher sind auch seltene gravierende Nebenwirkungen für Strahlentherapeuten relevant.

Material und Methoden

Wir berichten von einer Patientin mit Glioblastoma multiforme, die während der Radiochemotherapie mit TMZ eine medikamentös-toxische Hepatitis entwickelte.

Ergebnisse

In der 5. Behandlungswoche kam es zum Anstieg der Transaminasen und nachfolgend zu einem Ikterus, der sich erst nach 2 Monaten zurückbildete, was dem Bild der hepatitisch-cholestatischen Mischform der medikamentös-toxischen Hepatitis entspricht. Wesentliche Komplikationen ergaben sich nicht. In der Literatur sind vereinzelt enzephalopathische und fatale Verläufe beschrieben.

Schlussfolgerung

Bei der Behandlung mit TMZ ist eine 2-mal wöchentliche Kontrolle der Leberenzyme und Cholestaseparameter erforderlich, um fatale Verläufe einer toxischen Hepatitis zu vermeiden.     

Mirroring and mu rhythm involvement in social cognition: Are there dissociable subcomponents of theory of mind?

Tager-Flusberg and Sullivan [Tager-Flusberg, H., Sullivan, K., 2000. A componential view of theory of mind: evidence from Williams syndrome. Cognition 76, 59–90] have argued for a distinction between the social-perceptive component of theory of mind (ToM), involving judgment of mental state from facial and body expressions, and the social-cognitive component, which is representation-based and linked to language and theory-building. This is analogous to the distinction made by others [Gallese, V., Keysers, C., Rizzolatti, G., 2004. A unifying view of the basis of social cognition. Trends in Cognitive Science 8, 396–403] between representing the mental state of another as if it was one's own (simulation theory), which requires involvement of the mirror neuron system, and explicit or declarative reasoning about mental states (theory theory), which does not. This componential view of ToM was tested by examining mirroring, as indexed by EEG mu rhythm suppression, in subjects performing tasks assumed to tap both dimensions. Mu suppression was positively correlated with accuracy on the social-perceptual task but not in the social-cognitive task. In a ToM control task requiring judgments about person–object interactions accuracy was correlated with mu suppression. This implies that mirroring is involved in making judgments about emotions and person–object interactions. However, mirroring is insensitive to the distinction between correct and incorrect inferences in the social-cognitive task suggesting that additional mechanisms are needed to make mental attributions of beliefs and intentions. These results are consistent with a refined componential view of ToM.     

Similar exposure to a tobacco-specific carcinogen in smokeless tobacco users and cigarette smokers.

Smokeless tobacco has been proposed as a reduced risk substitute for smoking, but no large studies have investigated exposure to the powerful carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokeless tobacco users versus smokers. The purpose of this study was to carry out such a comparison. Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of NNK exposure, and cotinine, a biomarker of nicotine exposure, were quantified in the urine of 420 smokers and 182 smokeless tobacco users who were participants in studies designed to reduce their use of these products. The measurements were taken at baseline, before intervention. Levels of total NNAL per milliliter of urine were significantly higher in smokeless tobacco users than in smokers (P < 0.0001). When adjusted for age and gender, levels of total NNAL per milligram of creatinine were also significantly higher in smokeless tobacco users than in smokers (P < 0.001). Levels of cotinine per milliliter of urine and per milligram of creatinine were significantly higher in smokeless tobacco users than in smokers (P < 0.001). These results show similar exposures to the potent tobacco-specific carcinogen NNK in smokeless tobacco users and smokers. These findings do not support the use of smokeless tobacco as a safe substitute for smoking.     

Relationship of human toenail nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol to levels of these biomarkers in plasma and urine.

Recently, we developed sensitive and quantitative methods for analysis of the biomarkers of tobacco smoke exposure nicotine, cotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human toenails. In this study, we further evaluated the newly developed toenail biomarkers by investigating their relationship to demographic factors, reported exposure, plasma nicotine, cotinine, and trans-3'-hydroxycotinine, and urinary NNAL. Toenails of 105 smokers, mean age 38.9 years (range, 19-68), were analyzed. Fifty-five (53.4%) were male, with approximately equal numbers of Whites and African-Americans. The average number of cigarettes smoked per day was 18 (range, 5-50). There was no effect of age or gender on the toenail biomarkers. Toenail NNAL was higher in White than in African-American participants (P = 0.019). Toenail nicotine and toenail cotinine correlated significantly with cigarettes smoked per day (r = 0.24; P = 0.015 and r = 0.26; P = 0.009, respectively). Toenail nicotine correlated with plasma nicotine (r = 0.39; P < 0.001); toenail cotinine correlated with plasma cotinine (r = 0.45; P < 0.001) and plasma trans-3'-hydroxycotinine (r = 0.30; P = 0.008); and toenail NNAL correlated with urine NNAL (r = 0.53; P = 0.005). The results of this study provide essential validation data for the use of toenail biomarkers in investigations of the role of chronic tobacco smoke exposure in human cancer.     

Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation

Exposure of mammalian cells to UV radiation and other DNA-damagingagents triggers a response known as the UV response. This inductionresponse involves a large number of genes including c-jun, cell-cycleregulatory proteins, specific repair enzymes, and the tumorsuppressor gene p53. Altered expression of these genes followingDNA damage is hypothesized to result in G₁ arrest, thereby allowingcells to repair DNA damage prior to cell division. In the presentstudy, we investigated expression of the p53 gene in mouse keratinocytecell line 308 after exposure to UV-B light at a biologicallyrelevant dose. Irradiation of 308 cells with 40 J/m² UV-B resultedin a 4- to 10-fold induction in the level of p53 protein, peakingat 5 h post-irradiation. Northern blot analysis of RNA fromUV-B Irradiated cells showed no change in the steady-state levelof p53 mRNA following irradiation. However, the half-life ofp53 protein in UV-B irradiated 308 cells was extended     

Tumorigenicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a, l]pyrene (dibenzo[def, p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene

Diol epoxides of benzo[g]chrysene, dibenzo[a, l]pyrene (dibenzo[def,p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene weretested for tumorigenicity in newborn mice. The compounds testedwere racemic trans-11, 12-dihydroxy-anti-13,14-epoxy-11,12,13,14-tetrahydrobenzo[g]-chrysene(BgCDE), trans-11, 12-dihydroxy-anti-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a, l]PDE),trans-1,2-dihydroxy-anti-3,3a-epoxy-1,2,3,3a-tetrahydro-4H-cyclopenta[def]chrysene(C[def]C-1-3a-DE), trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8,9-tetrahydro-4H-cyclopenta-[def]chrysene(C[def]C-6-9-DE) and trans-2,3-dihydroxy-anti-1,10b-epoxy-10b,1,2,3-tetrahydrofluoranthene(FDE). BgCDE and DB[a,l]PDE are fjord region diol epoxides andtheir tumorigenic activities were compared to those of trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3,4-tetrahydrobenzo-[c]phenanthrene (BcPDE), a fjord region diolepoxide with known high tumorigenicity and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene(BPDE), a highly tumorigenic bay region diol epoxide. The protocolcalled for testing of each compound at a total dose of 25 nmolper mouse, administered on days 1, 7 and 15 of life, with killingat age 35 weeks. BgCDE had similar activity as BcPDE for inductionof lung tumors and was more active than BcPDE for inductionof liver tumors in male mice. Both compounds were significantlymore tumorigenic than BPDE. DB[a,l]PDE was highly toxic. Allmice died within 1 week of the first dose. It was then testedin a second study using total doses of 5 and 1 nmol per mouse.Only the first dose of the intended 5 nmol total dose was givendue to toxicity. The full course of doses with a total of 1nmol per mouse was administered; DB[a,l]PDE induced a significantincidence and multiplicity of lung tumors and, in male mice,liver tumors at both doses. These results demonstrate that fjordregion diol epoxides are highly active tumorigens in newbornmice, with activity greater than that of the most active unsubstitutedbay region diol epoxide, BPDE. C[def]C-1-3a-DE and C[def]-6-9-DEwere compared to trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene(CDE), at a total dose of 500 nmol per mouse. FDE was also testedat this dose. The most active compound among the chrysene derivativeswas C[def]C-1-3a-DE, followed by C[def]C-6-9-DE and CDE. C[def]C-1-3a-DEhas a sterically constrained bay region, in which the benzyliccarbon of the tri-substituted epoxide ring is part of a fusedring system. This feature is also present in FDE, which hadconsiderable tumorigenic activity, greater than that of CDEin lung and greater than any of the chrysene derivatives inliver. These results demonstrate that the tumorigenicity ofdiol epoxides in newborn mice is enhanced by steric constraintspresent when the epoxide ring is part of a fjord region or isattached to a fused ring system. The tumorigenic activity ofFDE may be relevant to human risk since it is a stable metaboliteof the widely distributed environmental pollutant fluoranthene.     

Comparative tumorigenicity of benzo[a]pyrene, 1-nitropyrene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine administered by gavage to female CD rats

Agents that are ubiquitous in the environment and are knowninducers of mammary cancer in rodents can be regarded as potentialcauses of human cancer and need to be evaluated more completely.Therefore, the purpose of this study was to determine underidentical conditions the relative carcinogenic potency in themammary glands of rats of benzo[a]pyrene (B[a]P), 1-nitropyrene(1-NP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyidne (PhIP).Thirty-day-old female CD rats were gavaged once weekly for 8weeks with B[a]P, 1-NP or PhIP. Each compound was given at 50µmol/rat/week in 0.5 ml trioctanoin for a total dose of400 µmoul/rat. Forty-one weeks after the last carcinogenadministration, rats were killed. In the 1-NP-treated rats,treatment elicited primarily benign tumors. In contrast, theB[a]P- and PhIP-treated rats developed both malignant and benigntumors. The incidence of adenocarcinomas in rats treated withB[a]P or PhIP was comparable and significantly higher than thatin animals receiving trioctanoin only. The incidence of benigntumors (fibroadenomas, desmoplastic adenomas and adenomas) observedin animals treated with B[a]P or 1-NP was comparable and significantlyhigher than that in animals given PhIP or trioctanoin. Thisis the first report describing the carcinogenic activity ofPhIP, given by gavage, in the mammary gland of CD rats and rankingthe carcinogenic potency observed under identical conditions,of three agents (B[a]P     

Neurological soft signs and neuropsychological performance in patients with first episode schizophrenia

Neurological soft signs and neuropsychological (NP) impairments are prevalent in schizophrenic patients. However, the relationship of these deficits is rarely studied, and it remains controversial in what way soft signs influence NP performance. The Neurological Evaluation Scale (NES) and a comprehensive neuropsychological test battery were used to assess soft signs and cognitive functions in 61 first-episode schizophrenic patients. The NP test battery included tests such as the California Verbal Learning Test, the Continuous Performance Test, the Span of Apprehension Test, the Stroop Color-Word Test, the Trail-Making Test and the Wisconsin Card Sorting Test. The NP tests were also administered to 87 healthy controls. The first-episode schizophrenic patients were split along the median of their NES total score (SS- vs. SS+). The level of NP performance and the differences in relative performance (shape of the NP profile) on NP functions between the two groups were assessed. The two groups (SS- vs. SS+) did not differ in any demographic or clinical variable. However, they differed in the level of their NP performance (profile mean) but did not show differential deficits in NP performance (profile shape). Neurologic soft signs influence NP performance and are correlated to a generalized NP deficit rather than to any specific NP functions.     

Not only training but also exposure to chlorinated compounds generates a response to oxidative stimuli in swimmers

Relations between exposure to chlorinated compounds and biological markers of response to oxidative stimuli were investigated in swimmers, taking into account the effect of training. Twenty-two male swimmers aged 15-25 years were surveyed twice. Prevalence of irritant symptoms and asthma and number of hours of training were reported. Exposure to nitrogen trichloride (NCl3) and blood response to oxidative stimuli [catalase, superoxide dismutase (Cu2+/Zn2+ SOD), glutathione peroxidase (GSH-Px) activities and ceruloplasmin, ferritin and total antioxidant concentrations] were measured. Univariate analyses were completed by multivariate analyses. High prevalences of irritant symptoms and asthma were found. Multivariate analysis confirmed the results of the univariate analyses and showed that Cu2+/Zn2+ SOD activity was increased by exposure and by training (P = 0.01, P = 0.0001, respectively). Erythrocyte GSH-Px was decreased, whereas plasma GSH-Px was increased by exposure (P = 0.002, P = 0.002). No other association was found. Higher irritant symptoms and increases in the activities of erythrocyte Cu2+/Zn2+ SOD and of plasma GSH-Px with exposure support the hypothesis that the production of reactive oxygen species is not only related to training but also to exposure to chlorinated compounds. Other athletes tend to have respiratory problems such as asthma, but the exposure to chlorinated compounds may increase the respiratory disease among swimmers.