Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer.

Gianni, Luca; Viganò, Lucia; Locatelli, Alberta; Capri, Giuseppe; Giani, Antonio; Tarenzi, Emiliana; Bonadonna, Gianni

doi:10.1200/jco.1997.15.5.1906

Cited by 244 publications

(126 citation statements)

References 0 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Cardiotoxicity was a major complication in initial trials combining 3-h infusions of paclitaxel with doxorubicin, with a 20% incidence of congestive cardiac failure reported (Gianni et al, 1995;Gehl et al, 1996). Pharmacokinetic studies have demonstrated increased plasma concentrations of doxorubicin and/or doxorubicinol when doxorubicin is given with paclitaxel (Holmes et al, 1996;Gianni et al, 1997a;Berg et al, 1994), and this may contribute to the increased risk of cardiac toxicity. Paclitaxel is formulated in 50% Cremophor EL (cremophor), which can result in similar alterations to doxorubicin pharmacokinetics when administered without paclitaxel (Millward et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of paclitaxel and epirubicin in advanced breast cancer

Rischin¹,

Smith

Millward³

et al. 2000

Br J Cancer

View full text Add to dashboard Cite

There has been considerable interest in determining the optimal way to combine the taxanes with anthracyclines, as these are the most active anti-cancer agents available for the treatment of advanced breast cancer (Hortobagyi and Holmes, 1997). Initial trials of 3-hour infusions of paclitaxel combined with doxorubicin reported high response rates, but significant cardiac toxicity (Gianni et al, 1995;Gehl et al, 1996). Epirubicin has similar efficacy to doxorubicin in breast cancer, with less cardiac toxicity (Bonadonna et al, 1993). Hence, combining paclitaxel with epirubicin may be one way of decreasing the risk of cardiac toxicity while maintaining efficacy. We have previously reported the results of a single-institution phase I trial of this combination in minimally pretreated patients, where the doses were escalated from epirubicin 60 mg m -2 and paclitaxel 155 mg m -2 to 90 mg m -2 and 200 mg m -2 respectively (Rischin et al, 1999). The dose-limiting toxicities were febrile neutropenia, oesophagitis and diarrhoea, and the recommended phase II doses were epirubicin 75 mg m -2 and paclitaxel 175 mg m -2 . In the current trial we have investigated the combination of paclitaxel and epirubicin in advanced breast cancer, using the recommended doses from our phase I trial. PATIENTS AND METHODS EligibilityPatients were required to have histologically proven advanced breast cancer. Patients may have received adjuvant chemotherapy but no prior chemotherapy for advanced disease. Prior anthracycline was permitted if at least 12 months had elapsed between completion of adjuvant treatment and relapse, and total doxorubicin dose was ≤240 mg m -2 . No prior taxane chemotherapy was permitted. Prior radiotherapy to less than 25% of the marrowbearing areas was permitted, but radiotherapy must have been completed at least 4 weeks prior to study entry. Patients had to have a bidimensionally measurable lesion with at least one diameter >1 cm. Other eligibility criteria were: age 18-75 years, performance status (ECOG) 0-2, absolute neutrophil count ≥ 2.0 × 10 9 l -1 , platelet count ≥ 100 × 10 9 l -1 , bilirubin ≤ upper limit of normal, transaminases ≤2 times upper limit of normal, serum creatinine ≤ 1.5 times upper limit of normal and left ventricular ejection fraction (LVEF) measured by radionuclide ventriculography ≥ lower limit of normal. Written informed consent was obtained from all patients and the protocol was approved by the Institutional Ethics Committees.Patients were excluded from the trial for any of the following: history of atrial or ventricular arrhythmias or cardiac failure, myocardial infarction within the preceding 6 months, history of second-or third-degree heart block, brain or bone metastases as the only known sites of disease, known bone-marrow metastases, pre-existing peripheral neuropathy > grade 2 by the Common Toxicity Criteria of the National Cancer Institute, history of other malignancy except for non-melanoma skin cancer or carcinoma in situ of the cervix, and pregnancy or lactation.The phase I and I...

show abstract

Section: Discussionmentioning

confidence: 99%

A phase II trial of paclitaxel and epirubicin in advanced breast cancer

Rischin¹,

Smith

Millward³

et al. 2000

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Cells were plated on 35-or 100-mm dishes in DMEM with 10% FCS and used when 70%-90% confluent. DOX was added to complete medium and incubated at 37°C for various intervals at a concentration (0.5 μg/ml) similar to plasma concentrations encountered in clinical use (30).…”

mentioning

confidence: 99%

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

172

239

View full text Add to dashboard Cite

The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

show abstract

“…The combination of PCX and anthracyclines has been also evaluated in several trials using a variety of doses and administration schedules, with studies showing drug interaction with respect to disposition and toxicity. Indeed, the PK studies of doxorubicin in regimens containing PCX have demonstrated that the schedule-dependent increase in C max and AUC and the reduction in doxorubicin clearance were associated with severe neutropaenia and mucositis (Holmes et al, 1996) as well as cardiac toxicity (Gianni et al, 1997). Furthermore, the addition of GEM to the PCX/anthracycline combination was associated with an increased incidence of severe neutropaenia ranging from 62 to 72% of patients (Sanchez-Rovira et al, 2000;Conte et al, 2001;Cappuzzo et al, 2004;Zielinski et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, up to 50% of patients receiving the PCX/ doxorubicin combination developed a reduction in the left ventricular ejection fraction (LVEF) below the normal level and 20% of them developed congestive heart failure (Gianni et al, 1995;Gehl et al, 1996). Several studies have suggested a sequencedependent tolerability because of altered pharmacokinetics (PKs) when PCX precedes doxorubicin administration (Holmes et al, 1996;Gianni et al, 1997).…”

mentioning

confidence: 99%

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours

et al. 2007

View full text Add to dashboard Cite

To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m À2 , respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m À2 , PCX 110 mg m À2 and GEM 1000 mg m À2 with neutropaenia being the doselimiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m À2 , PCX 100 mg m À2 and GEM 1000 mg m À2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours.

show abstract

Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer.

Cited by 244 publications

References 0 publications

A phase II trial of paclitaxel and epirubicin in advanced breast cancer

A phase II trial of paclitaxel and epirubicin in advanced breast cancer

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours

Contact Info

Product

Resources

About