Paclitaxel chemotherapy treatment often leads to neuropathic pain resistant to available analgesic treatments. Recently spinal Toll-like receptor 4 (TLR4) and the transient receptor potential cation channel subfamily V member 1 (TRPV1) were identified to be involved in the pro-nociceptive effect of paclitaxel. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinases in this process, with the use of their antagonists (wortmannin, LY-294002, and staurosporine). The single paclitaxel administration (8 mg/kg i.p.) in mice induced robust mechanical allodynia measured as a reduced threshold to von Frey filament stimulation and generated reduced tachyphylaxis of capsaicin-evoked responses, recorded as changes in mEPSC frequency in patch-clamp recordings of dorsal horn neurons activity in vitro, for up to eight days. Paclitaxel application also induced increased Akt kinase phosphorylation in rat DRG neurons. All these paclitaxel-induced changes were prevented by the wortmannin in vivo pretreatment. Acute co-application of wortmannin or LY-294002 with paclitaxel in spinal cord slices also attenuated the paclitaxel effect on capsaicin-evoked responses. Staurosporine was effective in the acute in vitro experiments and on the first day after the paclitaxel treatment in vivo, but in contrast to wortmannin, it did not have a significant impact later. Our data suggest that the inhibition of PI3K signaling may help alleviate pathological pain syndromes in the paclitaxel-induced neuropathy.
- MeSH
- buňky zadních rohů míšních účinky léků metabolismus MeSH
- excitační postsynaptické potenciály účinky léků MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- hyperalgezie chemicky indukované farmakoterapie metabolismus MeSH
- inhibitory proteinkinas farmakologie MeSH
- kapsaicin farmakologie MeSH
- kationtové kanály TRP MeSH
- kationtové kanály TRPV metabolismus MeSH
- krysa rodu rattus MeSH
- lipopolysacharidy farmakologie MeSH
- mícha účinky léků metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neuralgie chemicky indukované farmakoterapie metabolismus MeSH
- onkogenní protein v-akt metabolismus MeSH
- paclitaxel toxicita MeSH
- peptidové fragmenty imunologie metabolismus MeSH
- potkani Wistar MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory metabolismus MeSH
- proteinkinasa C imunologie metabolismus MeSH
- signální transdukce účinky léků MeSH
- toll-like receptor 4 metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Paclitaxel is used for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. In this study we examined the engagement of antioxidative signal pathway of the dorsal root ganglion (DRG) in mechanical and thermal hypersensitivity evoked by paclitaxel. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our results show that paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals. Paclitaxel also impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress, namely 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine. Systemic administration of SOD mimetic using tempol, antioxidant vitamin C or blocking oxidative pathway using NADPH oxidase inhibitor (GKT137831) attenuated mechanical and thermal hypersensitivity induced by paclitaxel. This inhibitory effect was accompanied with decreases of proinflammatory cytokines (PICs) such as IL-1beta, IL-6 and TNF-alpha in the DRG. In conclusion, the data revealed impairment of Nrf2-ARE and heightened oxidative and PIC signals in the DRG of paclitaxel rats, leading to neuropathic pain. Balancing of reactive oxygen species by supplying antioxidants and/or inhibiting NADPH oxidase appears significant to yield beneficial effects in neuropathic pain conditions after chemotherapeutic paclitaxel.
- MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- fytogenní protinádorové látky toxicita MeSH
- krysa rodu rattus MeSH
- měření bolesti účinky léků metody MeSH
- neuralgie chemicky indukované farmakoterapie metabolismus MeSH
- nocicepce účinky léků fyziologie MeSH
- paclitaxel toxicita MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
One of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy for several types of cancers. Our recent study showed that impairment of Nrf2-antioxidant response element (Nrf2-ARE) and upregulation of oxidative signals in the dorsal root ganglion (DRG) of rats with treatment of paclitaxel result in neuropathic pain. The purpose of this study was to examine the beneficial role played by electroacupuncture (EA) in modifying neuropathic pain evoked by paclitaxel via Nrf2-ARE and oxidative mechanisms. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-ARE and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our data showed that paclitaxel increased mechanical and thermal sensitivity and this was accompanied with impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress (i.e. 8-isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine). EA treatment largely restored the levels of Nrf2-ARE/SOD and inhibited products of oxidative stress and thereby attenuated mechanical and thermal hypersensitivity induced by paclitaxel. In conclusion, we revealed specific signaling pathways leading to paclitaxel-evoked neuropathic pain, including impairment of Nrf2-ARE and heightened oxidative signals. We further provided evidence for the role of EA in alleviating paclitaxel-neuropathic pain via these molecular mediators.
- MeSH
- antioxidancia * metabolismus MeSH
- elektroakupunktura metody MeSH
- fytogenní protinádorové látky toxicita MeSH
- krysa rodu rattus MeSH
- měření bolesti účinky léků metody MeSH
- neuralgie chemicky indukované metabolismus terapie MeSH
- paclitaxel toxicita MeSH
- potkani Sprague-Dawley MeSH
- signální transdukce účinky léků fyziologie MeSH
- spinální ganglia účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Autoři popisují případ polékového halucinatorního syndromu u 42leté pacientky s karcinomem prsu po infuzi paklitaxelu v rámci adjuvantní chemoterapie dle protokolu AC-T. Kazuistika poukazuje na potencionální riziko paklitaxelu ve smyslu psychotropního nežádoucího účinku a nutnost mezioborové spolupráce, konkrétně pak s psychiatrem. Časná symptomatická psychofarmakologická léčba umožnila bezproblémové dokončení adjuvantní chemoterapie.
The authors report on a case of drug-induced hallucinatory syndrome after paclitaxel infusion in a 42-year-old woman with breast carcinoma treated with adjuvant chemotherapy AC-T. This case report highlights the potential risk of paclitaxel causing hallucinatory syndrome. At the same time it indicates the need to cooperate with the psychiatrist. Early symptomatic psychopharmacological treatment enabled the smooth completion of chemotherapy.
- Klíčová slova
- chemoterapie, paklitaxel, psychotropní nežádoucí účinky, quetiapin,
- MeSH
- adjuvantní chemoterapie metody škodlivé účinky MeSH
- antipsychotika terapeutické užití MeSH
- dibenzothiazepiny farmakologie terapeutické užití MeSH
- docetaxel MeSH
- dospělí MeSH
- duktální karcinom prsu farmakoterapie chirurgie MeSH
- financování organizované MeSH
- fytogenní protinádorové látky škodlivé účinky MeSH
- halucinace chemicky indukované komplikace prevence a kontrola MeSH
- koordinovaný terapeutický postup MeSH
- lékové interakce MeSH
- lidé MeSH
- nádory prsu farmakoterapie chirurgie MeSH
- nemoci mozku chemicky indukované komplikace MeSH
- paclitaxel farmakologie škodlivé účinky toxicita MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky MeSH
- psychiatrie MeSH
- taxoidy škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Paclitaxel (PTX) is approved for the treatment of ovarian and breast cancer. The commercially available preparation of PTX, Cremophor EL(R) is associated with hypersensitivity reactions in spite of a suitable premedication. In general, the developed liposomal PTX formulations are troubled with low PTX encapsulation capacity (maximal content, 3 mol%) and accompanied by PTX crystallisation. The application of "pocket-forming" lipids significantly increased the encapsulation capacity of PTX in the liposomes up to 10 mol%. Stable lyophilised preparation of PTX (7 mol%) encapsulated in the liposomes composed of SOPC/POPG/MOPC (molar ratio, 60:20:20) doped with 5 mol% vitamin E had the size distribution of 180-190 nm (PDI, 0.1) with zeta-potential of -31 mV. Sucrose was found to be a suitable cryoprotectant at the lipid:sugar molar ratios of 1:5-1:10. This liposomal formulation did not show any evidence of toxicity in C57BL/6 mice treated with the highest doses of PTX (100 mg/kg administered as a single dose and 150 mg/kg as a cumulative dose applied in three equivalent doses in 48-h intervals). A dose-dependent anticancer effect was found in both hollow fibre implants and syngenic B16F10 melanoma mouse tumour models.
- MeSH
- fytogenní protinádorové látky aplikace a dávkování chemie terapeutické užití toxicita MeSH
- lipidy chemie MeSH
- liposomy MeSH
- lyofilizace MeSH
- melanom experimentální farmakoterapie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nanotechnologie MeSH
- paclitaxel aplikace a dávkování chemie terapeutické užití toxicita MeSH
- příprava léků MeSH
- stabilita léku MeSH
- velikost částic MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ovarian carcinoma represents the most common cause of death from gynecological malignancies in Europe and North America, being the third most frequent and the first as to the mortality. The standard chemotherapeutical regimen for ovarian cancer involves the administration of platinum derivate (carboplatin, cisplatin), in advanced stage is platinum derivate combined with paclitaxel. Introducing chemoresistance testing of ovarian tumour cells may help to choose optimal chemotherapeutic drug and customize the individual chemotherapeutical regimens in patients. One of approaches of individualization of chemotherapy is in vitro chemosensitivity testing. In our study, we evaluated the cytotoxic effects of selected chemotherapeutics in cells isolated from ovarian tumours and ascites of individual patients. Panel of chemotherapeutics used in the study included cisplatin, paclitaxel, carboplatin, topotecan, gemcitabine and etoposide and their effects on cell viability were determined by the MTT assay. In the total number of 32 clinical samples of tumour and ascites cells, the highest sensitivity showed cells to topotecan, sensitivity to cisplatin was higher than to carboplatin and paclitaxel used in clinical practice showed most often only the marginal reactivity. Resistance to carboplatin and most of the time to gemcitabine and etoposide was commonly present. When the same test on cells that have been frozen for several weeks was repeated it was found that in 20 cases chemosensitivity increased while in 18 cases decreased. In remaining cases there was no change in reactivity to cytostatics. Moreover, chemosensitivity of cells isolated from solid tumour and ascites from the same patient did not show any significant difference with exaption of paclitaxel. Copyright 2010 Elsevier Ltd. All rights reserved.
- MeSH
- biologické modely MeSH
- chemorezistence * MeSH
- cisplatina toxicita MeSH
- deoxycytidin analogy a deriváty toxicita MeSH
- etoposid toxicita MeSH
- karboplatina toxicita MeSH
- karcinom * farmakoterapie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků * farmakoterapie MeSH
- paclitaxel toxicita MeSH
- protinádorové látky toxicita MeSH
- screeningové testy protinádorových léčiv MeSH
- topotekan toxicita MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- farmakoterapie metody normy MeSH
- karboplatina normy toxicita MeSH
- lidé MeSH
- nádory vaječníků farmakoterapie patologie MeSH
- nežádoucí účinky léčiv diagnóza etiologie MeSH
- paclitaxel normy toxicita MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
