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Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH
(2015) Mol Cancer Ther 14: 994-1003
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Antineoplastic Agents, Biological Transport, Cell Line, Tumor, Docetaxel, Humans, Liver, Liver-Specific Organic Anion Transporter 1, Male, Mice, Mice, Knockout, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Rats, Solute Carrier Organic Anion Transporter Family Member 1B3, Taxoids, Tubulin Modulators
Show Abstract · Added February 25, 2015
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.
©2015 American Association for Cancer Research.
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18 MeSH Terms
Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).
Lockhart AC, Reed CE, Decker PA, Meyers BF, Ferguson MK, Oeltjen AR, Putnam JB, Cassivi SD, Montero AJ, Schefter TE, American College of Surgeons Oncology Group
(2014) Ann Oncol 25: 1039-44
MeSH Terms: Adenocarcinoma, Adult, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Chemoradiotherapy, Adjuvant, Cisplatin, Disease-Free Survival, Docetaxel, Esophageal Neoplasms, Esophagogastric Junction, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoadjuvant Therapy, Panitumumab, Taxoids, Treatment Outcome
Show Abstract · Added March 27, 2014
BACKGROUND - Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%.
PATIENTS AND METHODS - From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0.
RESULTS - Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%).
CONCLUSIONS - Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended.
CLINICALTRIALSGOV IDENTIFIER - NCT00757172.
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20 MeSH Terms
Thrombotic microangiopathy during docetaxel, trastuzumab, and carboplatin chemotherapy for early-stage HER2+ breast cancer: a case report.
Iams W, Beckermann KE, Neff AT, Mayer IA, Abramson VG
(2013) Med Oncol 30: 568
MeSH Terms: Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Carboplatin, Chemotherapy, Adjuvant, Docetaxel, Female, Humans, Middle Aged, Receptor, ErbB-2, Taxoids, Thrombotic Microangiopathies, Trastuzumab
Show Abstract · Added March 7, 2014
Chemotherapy-induced thrombotic microangiopathy is a severe illness that has occurred in a small number of patients treated with carboplatin and combination of docetaxel and trastuzumab chemotherapy. We describe herein the case of a patient with stage IIB breast cancer who developed thrombotic microangiopathy after five cycles of carboplatin, docetaxel, and trastuzumab.
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13 MeSH Terms
Quality of life with advanced metastatic prostate cancer.
Resnick MJ, Penson DF
(2012) Urol Clin North Am 39: 505-15
MeSH Terms: Androgen Antagonists, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Bone Neoplasms, Denosumab, Diphosphonates, Disease Progression, Docetaxel, Health Status Indicators, Humans, Imidazoles, Male, Mitoxantrone, Prostatic Neoplasms, Quality of Life, Taxoids, Treatment Outcome, Zoledronic Acid
Show Abstract · Added March 5, 2014
The health-related quality-of-life (HRQOL) implications of advanced metastatic prostate cancer are variable. There are several different HRQOL instruments that measure domains germane to patients with advanced metastatic disease. The burden of prostate cancer is inversely related to the magnitude of HRQOL declines. Treatment with androgen deprivation therapy commonly results in HRQOL declines that have served as the impetus for intermittent therapy. Conversely, chemotherapeutic agents have been associated with improvements in functional status for men with castrate-resistant disease. Emerging therapies may result in significant HRQOL improvements in this population, and careful prospective evaluation of patient-reported outcomes will be required.
Copyright © 2012 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Phase I study of concurrent weekly docetaxel, high-dose intensity-modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for high-risk prostate cancer.
Chen RC, Rosenman JG, Hoffman LG, Chiu WK, Wang AZ, Pruthi RS, Wallen EM, Crane JM, Kim WY, Rathmell WK, Godley PA, Whang YE
(2012) BJU Int 110: E721-6
MeSH Terms: Aged, Androgen Antagonists, Antineoplastic Agents, Disease-Free Survival, Docetaxel, Dose-Response Relationship, Drug, Follow-Up Studies, Gonadotropin-Releasing Hormone, Humans, Male, Middle Aged, Neoplasm Staging, Prospective Studies, Prostate-Specific Antigen, Prostatic Neoplasms, Radiation-Sensitizing Agents, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated, Taxoids, Treatment Outcome
Show Abstract · Added October 17, 2015
UNLABELLED - Study Type - Therapy (phase 1) Level of Evidence 2a What's known on the subject? and What does the study add? High-risk and locally advanced prostate cancers are difficult to cure with the standard regimen of radiation therapy (RT) with concurrent androgen-deprivation therapy (ADT). Multiple studies have explored the addition of docetaxel chemotherapy in attempt to improve patient outcomes. Prior Phase I studies have shown that docetaxel 20 mg/m(2) is a safe dose, when given concurrently with 70 Gy of radiation. But current standard RT for prostate cancer uses higher doses, and it is unclear if concurrent chemotherapy is safe with modern RT. This is a Phase I study that explored the addition of concurrent docetaxel chemotherapy to modern RT (intensity-modulated RT to 78 Gy) plus ADT. The study showed that weekly docetaxel at 20 mg/m(2) is safe with modern RT. At a median follow-up of 2.2 years, biochemical progression-free survival was 94%. This triple-therapy regimen is safe and promising for further evaluation in prospective trials.
OBJECTIVE - •  To evaluate in a phase I trial, the feasibility of adding concurrent weekly docetaxel chemotherapy to high-dose intensity modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for treatment of high-risk prostate cancer.
PATIENTS AND METHODS - •  Patients with high-risk prostate cancer were treated with a luteinising hormone-releasing hormone agonist (starting 2-3 months before IMRT and lasting 2 years), IMRT of 78 Gy to the prostate and seminal vesicles, and weekly docetaxel during RT. •  All patients had computed tomography and bone scans to exclude metastatic disease. •  A standard 3 + 3 design was used for docetaxel dose escalation. Successive patients were treated on dose levels of 10, 15, and 20 mg/m(2) of weekly docetaxel.
RESULTS - •  In all, 18 patients participated in the study: 15 (83%) had Gleason 8-10 disease; the other three had either clinical T3 disease and/or a prostate-specific antigen (PSA) level of >20 ng/mL. •  Grade 3 diarrhoea (a defined dose-limiting toxicity, DLT) occurred in one patient in each of the first two dose levels. However, when the cohorts were expanded, no further DLT was seen. •  Weekly docetaxel at 20 mg/m(2) (dose level 3) was successfully given without DLT. •  No patient had grade 4 or 5 toxicity. •  At a median follow-up of 2.2 years, all patients achieved a PSA nadir of <1 ng/mL, including 13 patients who had an undetectable PSA level. The 2-year biochemical progression-free survival was 94%.
CONCLUSION - •  A dose of 20 mg/m(2) of weekly docetaxel given concurrently with high-dose IMRT and ADT appears safe for further study in patients with high-risk prostate cancer.
© 2012 BJU INTERNATIONAL.
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20 MeSH Terms
The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas.
Sehdev V, Katsha A, Ecsedy J, Zaika A, Belkhiri A, El-Rifai W
(2013) Cancer 119: 904-14
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Aurora Kinase A, Aurora Kinases, Azepines, Cell Cycle Checkpoints, Cell Survival, Docetaxel, Female, Gastrointestinal Neoplasms, Humans, Mice, Mice, Nude, Polyploidy, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Pyrimidines, Taxoids, Xenograft Model Antitumor Assays
Show Abstract · Added September 3, 2013
BACKGROUND - Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs.
METHODS - After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively.
RESULTS - By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P < .001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P < .01) was significantly enhanced with the combination treatment (P < .001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P < .001).
CONCLUSIONS - The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.
Copyright © 2012 American Cancer Society.
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21 MeSH Terms
Thick-tissue bioreactor as a platform for long-term organotypic culture and drug delivery.
Markov DA, Lu JQ, Samson PC, Wikswo JP, McCawley LJ
(2012) Lab Chip 12: 4560-8
MeSH Terms: Bioreactors, Cell Culture Techniques, Cells, Cultured, Docetaxel, Drug Delivery Systems, Epithelial Cells, Equipment Design, Humans, Microfluidic Analytical Techniques, Peptide Hydrolases, Protease Inhibitors, Structure-Activity Relationship, Taxoids
Show Abstract · Added March 7, 2014
We have developed a novel, portable, gravity-fed, microfluidics-based platform suitable for optical interrogation of long-term organotypic cell culture. This system is designed to provide convenient control of cell maintenance, nutrients, and experimental reagent delivery to tissue-like cell densities housed in a transparent, low-volume microenvironment. To demonstrate the ability of our Thick-Tissue Bioreactor (TTB) to provide stable, long-term maintenance of high-density cellular arrays, we observed the morphogenic growth of human mammary epithelial cell lines, MCF-10A and their invasive variants, cultured under three-dimensional (3D) conditions inside our system. Over the course of 21 days, these cells typically develop into hollow "mammospheres" if cultured in standard 3D Matrigel. This complex morphogenic process requires alterations in a variety of cellular functions, including degradation of extracellular matrix that is regulated by cell-produced matrix proteinases. For our "drug" delivery testing and validation experiments we have introduced proteinase inhibitors into the fluid supply system, and we observed both reduced proteinase activity and inhibited cellular morphogenesis. The size inhibition results correlated well with the overall proteinase activities of the tested cells.
1 Communities
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13 MeSH Terms
Is renal thrombotic angiopathy an emerging problem in the treatment of ovarian cancer recurrences?
Kwa M, Baumgartner R, Shavit L, Barash I, Michael J, Puzanov I, Kopolovic J, Rosengarten O, Blank S, Curtin JP, Gabizon A, Muggia F
(2012) Oncologist 17: 1534-40
MeSH Terms: Adult, Aged, Antibodies, Monoclonal, Humanized, Bevacizumab, Creatinine, Deoxycytidine, Doxorubicin, Fatal Outcome, Female, Humans, Middle Aged, Ovarian Neoplasms, Platinum, Polyethylene Glycols, Quality of Life, Recurrence, Renal Insufficiency, Chronic, Retrospective Studies, Risk Factors, Taxoids, Thrombosis, Topotecan
Show Abstract · Added March 5, 2014
BACKGROUND AND OBJECTIVE - Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions.
PATIENTS AND METHODS - Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines.
RESULTS - Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy.
CONCLUSIONS - CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.
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22 MeSH Terms
Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis.
Park SI, Liao J, Berry JE, Li X, Koh AJ, Michalski ME, Eber MR, Soki FN, Sadler D, Sud S, Tisdelle S, Daignault SD, Nemeth JA, Snyder LA, Wronski TJ, Pienta KJ, McCauley LK
(2012) Cancer Res 72: 2522-32
MeSH Terms: Animals, Antineoplastic Agents, Alkylating, Bone Marrow, Bone Neoplasms, Cell Line, Tumor, Chemokine CCL2, Cyclophosphamide, Docetaxel, Humans, Interleukin-6, Male, Mice, Myeloid Cells, Neoplasm Transplantation, Prostatic Neoplasms, Taxoids
Show Abstract · Added March 5, 2014
A number of cancers predominantly metastasize to bone, due to its complex microenvironment and multiple types of constitutive cells. Prostate cancer especially has been shown to localize preferentially to bones with higher marrow cellularity. Using an experimental prostate cancer metastasis model, we investigated the effects of cyclophosphamide, a bone marrow-suppressive chemotherapeutic drug, on the development and growth of metastatic tumors in bone. Priming the murine host with cyclophosphamide before intracardiac tumor cell inoculation was found to significantly promote tumor localization and subsequent growth in bone. Shortly after cyclophosphamide treatment, there was an abrupt expansion of myeloid lineage cells in the bone marrow and the peripheral blood, associated with increases in cytokines with myelogenic potential such as C-C chemokine ligand (CCL)2, interleukin (IL)-6, and VEGF-A. More importantly, neutralizing host-derived murine CCL2, but not IL-6, in the premetastatic murine host significantly reduced the prometastatic effects of cyclophosphamide. Together, our findings suggest that bone marrow perturbation by cytotoxic chemotherapy can contribute to bone metastasis via a transient increase in bone marrow myeloid cells and myelogenic cytokines. These changes can be reversed by inhibition of CCL2.
©2012 AACR.
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16 MeSH Terms
Do the genes tell us the path of most resistance?
Balko JM, Black EP
(2011) Cancer Biol Ther 11: 213-5
MeSH Terms: Cell Line, Tumor, Docetaxel, Drug Resistance, Neoplasm, Humans, Male, Oligonucleotide Array Sequence Analysis, Prostatic Neoplasms, Taxoids
Added March 5, 2014
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8 MeSH Terms