Hepatotoxicity and metabolism of trabectedin: a literature review

Beumer, Jan H.; Schellens, J.H.M.; Beijnen, Jos H.

doi:10.1016/j.phrs.2004.12.001

Cited by 36 publications

(25 citation statements)

References 33 publications

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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).…”

Section: Resultsmentioning

confidence: 99%

“…Although trabectedin has impressive antitumor activity, dose-limiting hepatotoxicity became apparent during several clinical trials (reviewed in ref. 5).…”

mentioning

confidence: 99%

“…16). In addition, it has been suggested that the anti-inflammatory properties of dexamethasone could be responsible for the protection from trabectedin-mediated hepatotoxicity (5).…”

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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%

“…Although trabectedin has impressive antitumor activity, dose-limiting hepatotoxicity became apparent during several clinical trials (reviewed in ref. 5).…”

mentioning

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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“…The majority of patients (75%) did not require dose reductions. Anti-emesis prophylaxis included ondansetron and corticosteroids (beside their antimimetic activity, it is proved that corticosteroids decrease hepatotoxicity, which is likely to occur during trabectedin treatment [8,13,14]). …”

Section: Methodsmentioning

confidence: 99%

“…All patients were previously treated with chemotherapy. R Re es su ul lt ts s: : 120 courses of trabectedin were given (median 4, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. We were able to assess the response in 24 patients.…”

mentioning

confidence: 99%

Trabectedin in patients with pre-treated advanced soft tissue sarcoma: a retrospective single center analysis

Koseła¹,

Wiater²,

Świtaj³

et al. 2011

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Myeloid cells in hepatocellular carcinoma

et al. 2015

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Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), are abundant in HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC, and focus on their immune suppressive activities and tumor promoting functions, as well as the relevance to potential new therapies in HCC.

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Hepatotoxicity and metabolism of trabectedin: a literature review

Cited by 36 publications

References 33 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

Trabectedin in patients with pre-treated advanced soft tissue sarcoma: a retrospective single center analysis

Myeloid cells in hepatocellular carcinoma

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