508 research outputs found
Is membranous location of EGFR or EGFRvIII immunostaining associated with good prognosis in renal cell carcinoma?
NK105, a paclitaxel-incorporating micellar nanoparticle formulation, can extend in vivo antitumour activity and reduce the neurotoxicity of paclitaxel
Paclitaxel (PTX) is one of the most effective anticancer agents. In clinical practice, however, high incidences of adverse reactions of the drug, for example, neurotoxicity, myelosuppression, and allergic reactions, have been reported. NK105, a micellar nanoparticle formulation, was developed to overcome these problems and to enhance the antitumour activity of PTX. Via the self-association process, PTX was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interactions between the drug and the well-designed block copolymers for PTX. NK105 was compared with free PTX with respect to their in vitro cytotoxicity, in vivo antitumour activity, pharmacokinetics, pharmacodynamics, and neurotoxicity. Consequently, the plasma area under the curve (AUC) values were approximately 90-fold higher for NK105 than for free PTX because the leakage of PTX from normal blood vessels was minimal and its capture by the reticuloendothelial system minimised. Thus, the tumour AUC value was 25-fold higher for NK105 than for free PTX. NK105 showed significantly potent antitumour activity on a human colorectal cancer cell line HT-29 xenograft as compared with PTX (P<0.001) because the enhanced accumulation of the drug in the tumour has occurred, probably followed by its effective and sustained release from micellar nanoparticles. Neurotoxicity was significantly weaker with NK105 than with free PTX. The neurotoxicity of PTX was attenuated by NK105, which was demonstrated by both histopathological (P<0.001) and physiological (P<0.05) methods for the first time. The present study suggests that NK105 warrants a clinical trial for patients with metastatic solid tumours
Berberine modulates expression of mdr1 gene product and the responses of digestive track cancer cells to Paclitaxel
Berberine is the major constituent of Coptis chinese and is commonly used in Chinese herbal medicine to treat patients with gastrointestinal disorders. In this study, using flow cytometry, we have found that a 24-h berberine treatment up-regulated the multidrug-resistant transporter (pgp-170) expression in two oral (KB, OC2), two gastric (SC-M1, NUGC-3) and two colon (COLO 205, CT 26) cancer cell lines. Decreased retention of rhodamine 123 was observed in berberine-treated cells as compared to vehicle control. To examine whether the berberine modulated pgp-170 expression in cancer cells is associated with changes in drug resistance, we determined the cytotoxicity, cell cycle progression and cell morphology of Paclitaxel-treated cells. Paclitaxel (1 nMβ10 ΞΌM) treatment for 24 h induced cytotoxicity in OC2, SC-M1 and COLO 205 cells in a dose-dependent manner. Pretreatment of cells with 32 ΞΌM berberine for 24 h prior to Paclitaxel treatment resulted in increased viability as compared to that of Paclitaxel-treated cells. In addition, Paclitaxel-induced apoptosis and/or G2/M arrest in these three cancer cell lines. Pretreatment of cells with berberine prior to Paclitaxel blocked the Paclitaxel-induced cell cycle responses and morphological changes. These results together suggest that berberine modulated the expression and function of pgp-170 that leads to reduced response to Paclitaxel in digestive track cancer cells. Β© 1999 Cancer Research Campaig
Severe skin reaction secondary to concomitant radiotherapy plus cetuximab
The therapeutic use of monoclonal antibodies against the epidermal growth factor receptor (EGFR) is specifically associated with dermatologic reactions of variable severity. Recent evidence suggests superiority of the EGFR inhibitor (EGFRI) cetuximab plus radiotherapy compared to radiotherapy alone in patients with squamous cell carcinoma of the head and neck. Although not documented in a study population, several reports indicate a possible overlap between radiation dermatitis and the EGFRI-induced skin rash. We here present a case of severe skin reaction secondary to the addition of cetuximab to radiotherapy
Phase I/II study of DHAβpaclitaxel in combination with carboplatin in patients with advanced malignant solid tumours
DHAβpaclitaxel is a conjugate of paclitaxel and the fatty acid, docosahexaenoic acid. Preclinical studies have demonstrated increased activity, relative to paclitaxel, with the potential for an improved therapeutic ratio. We conducted a phase I study to determine the maximum tolerated doses of DHAβpaclitaxel and carboplatin when administered in combination. Two cohorts of patients were treated: carboplatin AUC 5 with DHAβpaclitaxel 660 mg m-2 and carboplatin AUC 5 with DHAβpaclitaxel 880 mg m-2. Both drugs were given on day 1 every 21 days. A total of 15 patients were enrolled with a median age of 59 years (range 33β71). All patients had advanced cancer refractory to standard treatment, performance status 0β2 and were without major organ dysfunction. A total of 54 cycles of treatment were delivered. No dose-limiting toxicity (DLT) was seen in the first cohort of three patients. In an expanded second cohort, neutropenia was the main DLT, occurring in the first cycle of treatment in five of 12 patients: three of these patients and one additional patient also experienced dose-limiting grade 3 transient rises in liver transaminases. No alopecia was seen and one patient developed clinically significant neuropathy. One partial response was seen in a patient with advanced adenocarcinoma of the oesophago-gastric junction and 12 patients had stable disease with a median time to progression of 184 days (range 60β506 days). The recommended phase II dose in pretreated patients is Carboplatin AUC 5 and DHAβpaclitaxel 660 mg m-2 given every 21 days. Further studies with Carboplatin AUC 5 and DHA-paclitaxel 880 mg m-2, given every 28 days, are warranted in chemo-naive patients
A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation
This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10βmgβmβ2, and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180βmgβmβ2. No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180βmgβmβ2 (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180βmgβmβ2. A partial response was observed in one patient with pancreatic cancer. The maximum concentration (Cmax) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150βmgβmβ2 was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150βmgβmβ2 every 3 weeks. The results of this phase I study warrant further clinical evaluation
Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens
Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone
NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel
NK105 is a micellar nanoparticle formulation designed to enhance the delivery of paclitaxel (PTX) to solid tumours. It has been reported to exert antitumour activity in vivo and to have reduced neurotoxicity as compared to that of free PTX. The purpose of this study was to investigate the radiosensitising effect of NK105 in comparison with that of PTX. Lewis lung carcinoma (LLC)-bearing mice were administered a single intravenous (i.v.) injection of PTX or NK105; 24βh after the drug administration, a proportion of the mice received radiation to the tumour site or lung fields. Then, the antitumour activity and lung toxicity were evaluated. In one subset of mice, the tumours were excised and specimens were prepared for analysis of the cell cycle distribution by flow cytometry. Combined NK105 treatment with radiation yielded significant superior antitumour activity as compared to combined PTX treatment with radiation (P=0.0277). On the other hand, a histopathological study of lung sections revealed no significant difference in histopathological changes between mice treated with PTX and radiation and those treated with NK105 and radiation. Flow-cytometric analysis showed that NK105-treated LLC tumour cells showed more severe arrest at the G2/M phase as compared to PTX-treated tumour cells. The superior radiosensitising activity of NK105 was thus considered to be attributable to the more severe cell cycle arrest at the G2/M phase induced by NK105 as compared to that induced by free PTX. The present study results suggest that further clinical trials are warranted to determine the efficacy and feasibility of combined NK105 therapy with radiation
Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies
Skin toxicity, a common drug-related adverse event observed in cancer patients treated with epidermal growth factor receptor (EGFR)-directed therapies is rarely seen with therapies targeting HER2. This study reports the significance of the EGFR and HER2 dimerization status in skin with regard to these dermatologic side effects. We demonstrate the differential effect of HER-directed therapies on the ligand driven activation status of EGFR, HER2 and MAPK in normal human epidermal keratinocytes. EGFR-directed therapies, such as gefitinib and cetuximab, inhibited ligand-induced activation of EGFR and MAPK in human keratinocytes. Pertuzumab, an antibody interfering with functional HER2 heterodimerization, failed to block ligand-induced HER signaling in primary keratinocytes. Using a novel proximity-based dimerization assay (eTagβ’) we show that EGFR homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies. The presence of [p]EGFR and [p]MAPK, but the absence of [p]HER2, demonstrates productive signaling via EGFR but not HER2 in human skin. These data illustrate the importance of the EGFR dimerization partner in human skin and suggests that inhibition of EGFR homodimer signaling rather than EGFR/HER2 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between EGFR-targeted versus HER2-targeted therapies
A phase I and pharmacokinetic study of novel taxane BMS-188797 and cisplatin in patients with advanced solid tumours
This phase I study investigated the maximum tolerated dose and pharmacokinetics of a 3-weekly administration of BMS-188797, a paclitaxel derivate, at three dose levels (DLs) (80, 110 and 150βmgβmβ2 DL), combined with cisplatin (standard dose 75βmgβmβ2). In 16 patients with advanced malignancies treated, one patient experienced dose-limiting febrile neutropenia, sepsis and severe colitis at the 150βmgβmβ2 DL; at the 110βmgβmβ2 DL one episode of dose-limiting grade 3 diarrhoea/nausea occurred. Grade 3/4 haematological toxicities were leucopenia/neutropenia; grade 3 nonhaematological toxicities were neuropathy, nausea, diarrhoea and stomatits. Objective response was seen in four patients, with three complete remissions in ovarian and cervical cancer patients. Pharmacokinetics of BMS-188797 appeared linear through the 110βmgβmβ2, but not through the 150βmgβmβ2 DL. The meanΒ±SD values for clearance, distribution volume at steady state and terminal half-life during cycle 1 were 317Β±60βmlβminβ1βmβ2, 258Β±96βlβmβ2 and 30.8Β±7.7βh, respectively. The maximum tolerated and recommended phase II dose for BMS-188797 was 110βmgβmβ2 (1-h infusion, every 3 weeks) combined with cisplatin 75βmgβmβ2
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