Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic  Breast Cancer

Grasselli, Giacomo; Viganò, Lucia; Capri, Giuseppe; Locatelli, Alberta; Tarenzi, Emiliana; Spreafico, Carlo; Bertuzzi, Alexia; Giani, Antonio; Materazzo, Carlo; Cresta, Sara; Perotti, Antonella; Valagussa, Pinuccia; Gianni, Luca

doi:10.1200/jco.2001.19.8.2222

Cited by 38 publications

(24 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This figure is significantly higher than that determined for EPI single agent or in combination with agents other than taxanes (15% cumulative risk of CHF at 1000 mg/m 2 EPI) (Ryberg et al, 1998), and it raises the possibility that PTX might increase the cardiotoxicity of EPI the same way it increases that of DOX. Interestingly, pharmacokinetic studies of patients receiving bolus EPI followed immediately by PTX infusion showed that PTX increased plasma exposure to EPIol and to the more polar EPIol or EPI glucuronides without affecting EPI elimination, a result pointing to metabolic rather than pharmacokinetic interference of PTX with EPI (Grasselli et al, 2001).…”

Section: Enhancement By Other Agentsmentioning

confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

Self Cite

View full text Add to dashboard Cite

Section: Enhancement By Other Agentsmentioning

confidence: 99%

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

et al. 2004

Self Cite

View full text Add to dashboard Cite

“…Retention times were 11.7 min (doxorubicinol), 12.4 min (doxorubicin), 14.1 min (AL1576), 18.9 min (docetaxel), and 20.6 min (paclitaxel). Anthracyclines were detected fluorimetrically (excitation at 480 nm, emission at 560 nm) (Salvatorelli et al, 2006); paclitaxel and docetaxel were detected by UV absorbance ( max ϭ 230 nm) (Grasselli et al, 2001); and AL1576 was detected by UV absorbance ( max ϭ 270 nm) and fluorescence (excitation at 280 nm, emission at 333 nm) (Barski et al, 1995). All the analytes were quantified against standard curves obtained after comparable extractive and chromatographic procedures.…”

Section: Methodsmentioning

confidence: 99%

Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

Salvatorelli

Menna

Cascegna

et al. 2006

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Antitumor therapy with the anthracycline doxorubicin is limited by a dose-related cardiotoxicity that is aggravated by a concomitant administration of the taxane paclitaxel. Previous limited studies with isolated human heart cytosol showed that paclitaxel was able to stimulate an NADPH-dependent reduction of doxorubicin to its toxic secondary alcohol metabolite doxorubicinol. Here we characterized that 0.25 to 2.5 M paclitaxel caused allosteric effects that increased doxorubicinol formation in human heart cytosol, whereas 5 to 10 M paclitaxel decreased doxorubicinol formation. The closely related taxane docetaxel caused similar effects. Basal or taxane-stimulated doxorubicinol formation was blunted by 2,7-difluorospirofluorene-9,5Ј-imidazolidine-2Ј,4Ј-dione (AL1576), a specific inhibitor of aldehyde reductases. Doxorubicinol was measured also in the cytosol of human myocardial strips incubated in plasma and exposed to doxorubicin in the absence or presence of paclitaxel or docetaxel and their clinical vehicles Cremophor EL or polysorbate 80. Low concentrations of taxanes stimulated doxorubicinol formation, whereas high concentrations decreased it. Doxorubicinol formation reached its maximum on adding plasma with 6 M paclitaxel or docetaxel; this corresponded to the partitioning of 1.5 to 2.5 M taxanes in the cytosol of the strips. Taxane-stimulated doxorubicinol formation was not mediated by vehicles, nor was it caused by increased doxorubicin uptake or de novo protein synthesis; however, doxorubicinol formation was blunted by AL1576. These results show that allosteric interactions with cytoplasmic aldehyde reductases enable paclitaxel or docetaxel to stimulate doxorubicinol formation in human heart. This information serves metabolic insights into the risk of cardiotoxicity induced by doxorubicin-taxane therapies.The anthracycline doxorubicin and the taxane paclitaxel are both highly active in breast cancer. Doxorubicin and paclitaxel exhibit different mechanisms of action (DNA intercalation and topoisomerase II inhibition versus microtubule stabilization), nonoverlapping toxicities (cardiomyopathy versus neuropathy), and incomplete cross-resistance;

show abstract

“…These concentrations were severalfold lower than in previous studies of rabbit isolated heart (10, 11) but ranged over levels measured in the plasma of patients shortly after standard boluses of DOX (27) or EPI (28). Moreover, all experiments were reconstituted in fresh plasma from healthy donors to account for the known ability of albumin and ␣-acid glycoprotein to bind anthracyclines and limit their partitioning in tissues (29).…”

Section: Characterization Of a Translational Model Of Humanmentioning

confidence: 76%

Defective One- or Two-electron Reduction of the Anticancer Anthracycline Epirubicin in Human Heart

Salvatorelli

Guarnieri

Menna

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

One-electron quinone reduction and two-electron carbonyl reduction convert the anticancer anthracycline doxorubicin to reactive oxygen species (ROS) or a secondary alcohol metabolite that contributes to inducing a severe form of cardiotoxicity. The closely related analogue epirubicin induces less cardiotoxicity, but the determinants of its different behavior have not been elucidated. We developed a translational model of the human heart and characterized whether epirubicin exhibited a defective conversion to ROS and secondary alcohol metabolites. Small myocardial samples from cardiac surgery patients were reconstituted in plasma that contained clinically relevant concentrations of doxorubicin or epirubicin. In this model only doxorubicin formed ROS, as detected by fluorescent probes or aconitase inactivation. Experiments with cell-free systems and confocal laser scanning microscopy studies of H9c2 cardiomyocytes suggested that epirubicin could not form ROS because of its protonation-dependent sequestration in cytoplasmic acidic organelles and the consequent limited localization to mitochondrial one-electron quinone reductases. Accordingly, blocking the protonation-sequestration mechanism with the vacuolar H ؉ -ATPase inhibitor bafilomycin A1 relocalized epirubicin to mitochondria and increased its conversion to ROS in human myocardial samples. Epirubicin also formed ϳ60% less alcohol metabolites than doxorubicin, but this was caused primarily by its higher K m and lower V max values for two-electron carbonyl reduction by aldo/ketoreductases of human cardiac cytosol. Thus, vesicular sequestration and impaired efficiency of electron addition have separate roles in determining a defective bioactivation of epirubicin to ROS or secondary alcohol metabolites in the human heart. These results uncover the molecular determinants of the reduced cardiotoxicity of epirubicin and serve mechanism-based guidelines to improving antitumor therapies. The anthracyclines doxorubicin (DOX)4 and epirubicin (EPI) are topoisomerase II inhibitors that exhibit activity in breast cancer and many other tumors (1). These drugs are composed of an aglycone and a sugar. The aglycone (doxorubicinone) consists of a tetracyclic ring with adjacent quinone-hydroquinone moieties and a short side chain with a carbonyl group; the sugar (daunosamine) is an amino-substituted trideoxy fucosyl moiety. Epirubicin differs from DOX in an axial-toequatorial epimerization of the hydroxyl group at C-4Ј in daunosamine (Fig. 1). This minor difference renders EPI a much better substrate than DOX for human liver UDP-glucuronosyltransferase 2B7 and consequently facilitates the formation of glucuronides that are excreted in bile and urine (2). Improved glucuronidation and body clearance alter the dose-related antiproliferative activity of EPI, as shown by the fact that the dose of EPI equimyelotoxic to 1 mg of DOX is 1.5 mg (3).A major obstacle to the clinical use of anthracyclines pertains to the development of cardiomyopathy and congestive heart failure upon chroni...

show abstract

Clinical and Pharmacologic Study of the Epirubicin and Paclitaxel Combination in Women With Metastatic Breast Cancer

Abstract: ET is feasible, devoid of excessive cardiac toxicity, and active. A reciprocal pharmacokinetic interference between the two drugs has pharmacodynamic consequences, and suggests a direct effect of PTX on EPI metabolism requiring ad hoc investigation.

Cited by 38 publications

References 20 publications

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

Paclitaxel and Docetaxel Stimulation of Doxorubicinol Formation in the Human Heart: Implications for Cardiotoxicity of Doxorubicin-Taxane Chemotherapies

Defective One- or Two-electron Reduction of the Anticancer Anthracycline Epirubicin in Human Heart

Contact Info

Product

Resources

About