TOXICITY STUDIES OF PACLITAXEL (I) : Single dose intravenous toxicity in rats

Kadota, Toshihito; Chikazawa, Hirotaka; Kondoh, Eiji; Ishikawa, Katsumi; Kawano, Shigeo; Kuroyanagi, Kohji; Hattori, Norimichi; Sakakura, Kayo; Koizumi, Shigeru; Hiraiwa, Eiko; Kohmura, Hisashi; Takahashi, Norimitsu

doi:10.2131/jts.19.supplementi_1

Cited by 8 publications

(6 citation statements)

References 5 publications

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“…This leads to the release of more ROS and pro‐ and anti‐inflammatory cytokines, which can induce an inflammatory response (Iwasaki & Gagnon, ). In the previous experimental studies, it was reported that the testicular atrophy with the suppression of spermatogenesis and the atrophy of tubules and epididymis were observed in the toxicity of paclitaxel (Kadota et al ., ,b). In a controlled clinical study designed to assess the effects of taxane‐based chemotherapy on the male reproductive axis, it was also reported that there was a decrease in inhibin B level, an increase in FSH level and a significant decrease in bilateral testicular volume in 95% of the patients in the early stages after the completion of chemotherapy (Chatzidarellis et al ., ).…”

Section: Discussionmentioning

confidence: 99%

“…Testicular tissue is rich in microtubule networks, which form the meiotic and mitotic spindles, and the Sertoli cell cytoskeleton, and are of great importance in spermatogenesis (Russel et al ., ). The toxic effect of paclitaxel on testis and epididymis is well known (Kadota et al ., ,b). This experimental study was designed to investigate whether DTX causes male reproductive toxicity and the protective effect of quercetin on such toxicity in an in vivo rat model.…”

Section: Introductionmentioning

confidence: 99%

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Quercetin prevents docetaxel-induced testicular damage in rats

et al. 2014

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The protective effect of quercetin on docetaxel - an anticancer agent - induced testicular damage in rats was investigated. Thirty-two rats were randomly divided into four groups: group 1 - control, carrier solutions were given; group 2 - quarcetin 20 mg kg(-1) day(-1) was given orally; group 3 - docetaxel 5 mg kg(-1) was given intraperitoneally as single dose; group 4 - docetaxel and quarcetin were given together. The histopathological changes; the specific biochemical markers, including antioxidants; and the sperm characteristics were evaluated. Docetaxel caused a significant increase in TBARS level and a significant decrease in SOD, GPX, CAT and GSH levels in the testicular tissues compared with the control group, whereas quercetin led to a significant decrease in lipid peroxidation, which was caused by docetaxel, via reducing TBARS level and increasing the levels of SOD, CAT, GPX and GSH. In addition, after docetaxel administration, sperm motility, sperm concentration, testicular and epididymis weights were significantly decreased and abnormal sperm rate and histopathological changes were increased. However, these effects of docetaxel on sperm parameters, histological changes and the tissue weights were eliminated by quercetin treatment. Our results show that the administration of docetaxel induced the testicular damage (oxidative stress, testes tissue damage and sperm parameters), and quercetin prevented docetaxel-induced testicular damage in rats.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quercetin prevents docetaxel-induced testicular damage in rats

et al. 2014

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“…In human cancer patients, taxol-induced lymphocyte toxicity (27), neutropenia (4), testicular shrinkage (28), and ovarian damage (29), are potentially correlated with the endogenous GT198 protein expression specifically in testis, ovary, spleen, and thymus (16,22). The acute taxol toxicity in rodents was also found in ovary (30), testis, hematopoietic, and lymphoid systems (31). In contrast, the low toxicity of taxol in major organs is correlated with undetectable GT198 protein level therein (16).…”

Section: Discussionmentioning

confidence: 99%

Oncoprotein GT198 is a direct target of taxol

Yang

Gurvich²,

Gupta

et al. 2019

Preprint

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Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbol PSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. The GT198 gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptormediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198 in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair.Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.

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“…A single dose of 85 mg/kg i.v. paclitaxel was reported to be lethal in 20 to 40% of Sprague-Dawley rats (Kadota et al, 1994). Incorporation of paclitaxel in liposomes increases the MTD of paclitaxel (Sharma et al, 1993), and so the above-reported dose was tested in rats bearing 14-day intracranial 9L tumors, as were doses that were approximately 20% higher and lower.…”

Section: Resultsmentioning

confidence: 99%

Differential Pharmacodynamic Effects of Paclitaxel Formulations in an Intracranial Rat Brain Tumor Model

Zhou¹,

Mazurchuk²,

Tamburlin³

et al. 2009

J Pharmacol Exp Ther

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Nano-and microparticulate carriers can exert a beneficial impact on the pharmacodynamics of anticancer agents. To investigate the relationships between carrier and antitumor pharmacodynamics, paclitaxel incorporated in liposomes (L-pac) was compared with the clinical standard formulated in Cremophor-EL/ethanol (Cre-pac) in a rat model of advanced primary brain cancer. Three maximum-tolerated-dose regimens given by intravenous administration were investigated: 50 mg/kg on day 8 (d8) after implantation of 9L gliosarcoma tumors; 40 mg/kg on d8 and d15; 20 mg/kg on d8, d11, and d15. Body weight change and neutropenia were assessed as pharmacodynamic markers of toxicity. The pharmacodynamic markers of antitumor efficacy were increase in lifespan (ILS) and tumor volume progression, measured noninvasively by magnetic resonance imaging. At equivalent doses, neutropenia was similar for both formulations, but weight loss was more severe for Cre-pac. No regimen of Cre-pac extended survival, whereas L-pac at 40 mg/kg ϫ2 doses was well tolerated and mediated 26% ILS (p Ͻ 0.0002) compared with controls. L-pac at a lower cumulative dose (20 mg/kg ϫ3) was even more effective (40% ILS; p Ͻ 0.0001). In striking contrast, the identical regimen of Cre-pac was lethal. Development of a novel semimechanistic pharmacodynamic model permitted quantitative hypothesis testing with the tumor volume progression data, and suggested the existence of a transient treatment effect that was consistent with sensitization or "priming" of tumors by more frequent L-pac dosing schedules. Therefore, improved antitumor responses of carrier-based paclitaxel formulations can arise both from dose escalation, because of reduced toxicity, and from novel carriermediated alterations of antitumor pharmacodynamic effects.The treatment of malignant brain tumors presents continuing challenges. Conventional therapy by surgical debulking and followed by radiation and chemotherapy generally is not curative. Chemotherapy fails for pathophysiological, pharmacological, and pharmaceutical reasons. Poor perfusion, tortuous and poorly permeable vasculature, and drug resistance are tumor properties that hinder drug penetration, deposition, and retention (Trédan et al., 2007). Suboptimal drug properties, including poor intrinsic membrane and tissue permeability, short circulating half-life, and rapid metabolism also impede therapy.Incorporation of drugs in particulate carriers such as emulsions, nanoparticles, or liposomes may provide the means to overcome several of these factors. By limiting the drug volume of distribution, the carrier can reduce toxicity to normal tissues, permitting higher doses and thereby overcoming functional resistance (Drummond et al., 1999). In addition, carriers may extravasate through the flawed tumor microvasculature, increasing drug deposition and antitumor effects (Sharma et al., 1997;Zhou et al., 2002;Arnold et al., 2005).Paclitaxel is a clinically important cytostatic/cytotoxic agent that also exerts potent antiangiogenic effects (Be...

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TOXICITY STUDIES OF PACLITAXEL (I) : Single dose intravenous toxicity in rats

Cited by 8 publications

References 5 publications

Quercetin prevents docetaxel-induced testicular damage in rats

Quercetin prevents docetaxel-induced testicular damage in rats

Oncoprotein GT198 is a direct target of taxol

Differential Pharmacodynamic Effects of Paclitaxel Formulations in an Intracranial Rat Brain Tumor Model

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