Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice

Beumer, Jan H.; Franke, N.; Tolboom, R.; Buckle, Tessa; Rosing, Hilde; López-Lázaro, Luis; Schellens, Jan H.M.; Beijnen, Jos H.; Tellingen, Olaf van

doi:10.1007/s10637-009-9234-8

Cited by 10 publications

(10 citation statements)

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“…Hepatotoxicity caused by trabectedin has been reported based on elevated blood levels of several markers, including alanine aminotransaminase, aspartate aminotransaminase, alkaline phosphatase, and bilirubin (5). Previous studies in mice indicated that according to these markers, the hepatotoxicity is maximal 3 days after trabectedin administration (28). CYP3A has been suggested to efficiently metabolize trabectedin in the liver, thereby reducing the hepatotoxic effects (8,9,12).…”

Section: Resultsmentioning

confidence: 99%

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ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity

Waterschoot

Eman²,

Wagenaar³

et al. 2009

Clinical Cancer Research

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Purpose: Trabectedin (Yondelis, ET-743) is a novel anticancer drug with potent activity against various tumors. However, dose-limiting hepatotoxicity was observed during clinical trials. Because recent reports have suggested that cytochrome P450 3A (CYP3A), as well as the drug transporters ABCB1, ABCC2, and ABCC3 might protect against trabectedin-mediated hepatotoxicity, we investigated the individual and combined roles of these detoxifying systems. Experimental Design: Madin-Darby canine kidney cells expressing ABCC2 and ABCC3 were used to study in vitro trabectedin transport. We investigated the hepatotoxicity of trabectedin, and the plasma and liver levels of this drug and its metabolites in mice deficient for CYP3A, Abcb1a/1b, Abcc2, and/or Abcc3 after i.v. trabectedin administration. Results: Trabectedin was transported by ABCC2 but only modestly by ABCC3. Contrary to our expectation, absence of CYP3A resulted in only a marginal increase in hepatotoxicity. Some hepatotoxicity was observed in Abcc2 -/-mice, but very little in Abcb1a/ 1b -/-and Abcc3 -/-mice. Strikingly, severe hepatotoxicity was found in Abcb1a/1b/ Abcc2 -/-and Abcc2/Abcc3 -/-mice. However, hepatotoxicity was drastically decreased in Cyp3a/Abcb1a/1b/Abcc2 -/-compared with Abcb1a/1b/Abcc2 -/-mice. This suggests that the formation of CYP3A-specific metabolites is an important prerequisite for trabectedin-mediated hepatotoxicity. Further studies revealed that there is increased accumulation of metabolites of trabectedin, but not of trabectedin itself, in the livers of mice that lack Abcc2 but are CYP3A proficient. Conclusions: Our data show that ABCB1, ABCC2, and ABCC3 have a profound and partially redundant function in protection from trabectedin-mediated hepatotoxicity, presumably by clearing the liver from hepatotoxic trabectedin metabolites that are primarily formed by CYP3A. (Clin Cancer Res 2009;15(24):7616-23) Trabectedin is an anticancer drug isolated from a marine tunicate that has recently been approved for the treatment of soft tissue carcinoma. In addition, several phases II and III clinical trials of trabectedin for treatment of other cancer types have been published or are still ongoing, including trials for breast (1), ovarian (2, 3), and prostate cancer (4). Although trabectedin has impressive antitumor activity, dose-limiting hepatotoxicity became apparent during several clinical trials (reviewed in ref. 5).Mass balance studies have revealed that trabectedin is extensively metabolized, and virtually all trabectedin is excreted in its metabolite form into bile. The chemical structure of trabectedin provides numerous sites for metabolic conversion. Indeed, a large number of (unknown) metabolites, without clearly predominating metabolites, could be observed in radiochromatograms after i.v. administration of ( 14 C)trabectedin to patients (6). No metabolites in plasma have been structurally identified so far and only a few metabolites from feces (6). The low dose and high volume of distribution, and long terminal half-l...

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Section: Resultsmentioning

confidence: 99%

“…After 40 min, cardiac puncture was done under anesthesia with methoxyflurane for three mice per time point. Forty minutes was selected based on previous pharmacokinetic studies with trabectedin in mice (28). Blood was collected in heparinized syringes, and plasma was obtained after centrifugation at 2,100 × g for 6 min.…”

Section: Translational Relevancementioning

confidence: 99%

ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity

Waterschoot

Eman²,

Wagenaar³

et al. 2009

Clinical Cancer Research

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“…After log-transformation, these ratios were subjected to a two-sided Students t -test, under the null hypothesis of log (AUC-ratio)=0. A value of p <0.05 was considered statistically significant, as described previously [13]. This approach is similar to that described by Bailer et al[14].…”

Section: Methodsmentioning

confidence: 99%

Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice

Parise

Beumer

Clausen

et al. 2013

Cancer Chemother Pharmacol

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Purpose Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram thereby shifting BA production from blood to tissues. Methods Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA and metabolites were quantitated in plasma and urine, and toxicities were assessed. Results BEN had a plasma t½ <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold, (AUC0-inf from 0.11 to 40.5 mg/L•min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0% to 1.5% of dose) while BA excretion was unchanged. Hematocrit, white blood cells counts and %lymphocytes decreased after BEN administration. Co-administration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN. Conclusions BEN plasma concentrations increased after administration of disulfiram, suggesting that ALDH mediates the rapid metabolism of BEN in vivo, which may explain the increased toxicity seen with BEN after administration of disulfiram. Our results suggest that the co-administration of BEN with drugs that inhibit ALDH or to patients that are ALDH deficient may cause liver damage.

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“…The majority of small-molecule anticancer drugs derived from natural products, including taxol and, recently reported, trabectedin, are substrates of drug transporters such as P-gp, MRP1, and/or BRCP, and their therapeutic effectiveness could be severely impaired by MDR mechanisms. 47, 48 One advantage of tanshinone-1, compared with those clinical drugs, is that its anticancer effect is independent of the MDR mechanism. Therefore, the compound is toxic to any cancer cells, even those with the expression of the MDR phenotype.…”

Section: Discussionmentioning

confidence: 99%

Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks

et al. 2013

Cell Death Dis

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Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.

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Disposition and toxicity of trabectedin (ET-743) in wild-type and mdr1 gene (P-gp) knock-out mice

Cited by 10 publications

References 39 publications

ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity

ABCC2, ABCC3, and ABCB1, but not CYP3A, Protect against Trabectedin-Mediated Hepatotoxicity

Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice

Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks

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