Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer

Sessa, Cristiana; Perotti, Antonella; Noberasco, Cristina; Braud, Filippo de; Gallerani, Elisa; Cresta, Stefania; Zucchetti, Massimo; Viganò, Lucia; Locatelli, Alberta; Jimeno, J.; Feilchenfeldt, Jonas; D’Incalci, Maurizio; Capri, Giuseppe; Ielmini, Nicoletta; Gianni, Luca

doi:10.1016/j.ejca.2008.11.019

Cited by 55 publications

(32 citation statements)

References 29 publications

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“…Trabectedin (previously known as ecteinascidin-743 or ET-743) is a novel and potent anticancer drug approved in Europe, Russia and South Korea for the treatment of patients with advanced soft tissue sarcoma who failed to respond to anthracycline or ifosfamide chemotherapy, or who are unsuited to receive these agents [338][339][340][341][342][343][344][345]. It is also undergoing clinical evaluations for the treatment of breast, prostate, and pediatric sarcomas.…”

Section: Trabectedinmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

144

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Section: Trabectedinmentioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

144

View full text Add to dashboard Cite

show abstract

“…Doxorubicin is the main agent used in STS so that the combination of trabectedin with doxorubicin was the most obvious choice for phase 1 clinical studies. Two studies used doxorubicin, one in advanced STS and breast cancer patients [35 ] and the other in STS patients only [36 ]. The latter was closed with a recommended dose of 1.1 mg/m 2 of trabectedin in combination with doxorubicin 60 mg/m 2 every 3 weeks, whereas the former recommended 0.7 mg/m 2 of trabectedin.…”

Section: Trabectedin In Combination In Sarcomamentioning

confidence: 99%

Trabectedin therapy for sarcomas

Casali¹,

Sanfilippo²,

D’Incalci³

2010

Current Opinion in Oncology

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“…Another Phase I trial of trabectedin combined with doxorubicin was recently published [48]. In this study, doxorubicin was administered at 60 mg/m 2 every 3 weeks and trabectedin was administered at increasing doses (0.1 mg/m 2 /dose level) starting at 0.6 mg/m 2 as a 3-h infusion every 3 weeks.…”

Section: Drug Profilementioning

confidence: 99%

Trabectedin for the management of soft-tissue sarcoma

Boudou

Baconnier

Blay

et al. 2009

Expert Review of Anticancer Therapy

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Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA-repair machinery. Trabectedin has shown promising single-agent activity in pretreated patients with soft-tissue sarcoma (STS) and ovarian and breast cancer; combination with various other chemotherapeutic drugs is feasible. Toxicities are mainly hematological and hepatic, with grade 3-4 neutropenia and thrombocytopenia observed in approximately 50 and 20% of patients, respectively, and grade 3-4 elevation of liver transaminases observed in 35-50% of patients treated with trabectedin. Trabectedin obtained regulatory approval by the EMEA and in other countries for the treatment of STS patients after failure of all available standard-of-care chemotherapy. Current research focuses on the identification of predictive factors for patients treated with trabectedin as well as the development of other combinations.

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Phase I clinical and pharmacokinetic study of trabectedin and doxorubicin in advanced soft tissue sarcoma and breast cancer

Cited by 55 publications

References 29 publications

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Trabectedin therapy for sarcomas

Trabectedin for the management of soft-tissue sarcoma

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