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1.
Eur J Cancer ; 75: 33-40, 2017 04.
Article in English | MEDLINE | ID: mdl-28214655

ABSTRACT

BACKGROUND: Recent phase II and III clinical trials demonstrated anti-tumour activity of eribulin, a tubulin-interacting cytotoxic agent, in patients with metastatic soft tissue sarcoma (STS). In this exploratory study, we aimed to identify putative microRNA biomarkers that associate with eribulin sensitivity or resistance in STS. MATERIALS AND METHODS: Archival tumour tissue from primary tumours or metastatic lesions was collected prior to eribulin treatment, from 65 consenting patients involved in the EORTC trial 62052. This phase II study (ClinicalTrials.gov identifier NCT00413192) included multiple subtypes of STS. Tissue was available from 21 leiomyosarcomas, 14 adipocytic sarcomas, 9 synovial sarcomas and 21 other sarcoma histotypes. Total RNA was isolated from formalin-fixed, paraffin-embedded tumour samples and analysed using Taqman® Low Density Arrays to determine microRNA expression profiles. The expression of a total of 756 microRNAs was assessed. Progression-free survival at week 12 (RECIST 1.0) measured as a binary variable, was the primary end-point of the clinical trial and used as a primary response measure for correlative studies. Seventeen of 53 (32.1%) evaluable patients in the analysed subset had non-progressive disease at week 12 and were defined as responders. RESULTS: The expression of 26 individual microRNAs (p < 0.05) differed significantly between non-responders and responders. Additional microRNAs of potential relevance were identified when considering the different histological subgroups. CONCLUSIONS: The expression level of particular microRNAs in STS tissue samples may predict response to eribulin. Further validation studies as well as a preclinical assessment of the underlying molecular mechanisms are required.


Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Furans/therapeutic use , Ketones/therapeutic use , MicroRNAs/metabolism , Neoplasms, Connective and Soft Tissue/drug therapy , Sarcoma/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Leiomyosarcoma/drug therapy , Liposarcoma/drug therapy , Male , Middle Aged , Treatment Outcome , Young Adult
2.
Br J Cancer ; 115(6): 674-81, 2016 09 06.
Article in English | MEDLINE | ID: mdl-27537383

ABSTRACT

BACKGROUND: Both taxanes, docetaxel and cabazitaxel, are effective treatments for metastatic castration-resistant prostate cancer (mCRPC). However, resistance to taxanes is common. Our objective was to investigate mechanisms of taxane resistance in prostate cancer. METHODS: Two docetaxel-resistant patient-derived xenografts (PDXs) of CRPC were established (PC339-DOC and PC346C-DOC) in male athymic nude mice by frequent intraperitoneal administrations of docetaxel. Next-generation sequencing was performed on PDX tissue pre- and post-docetaxel resistance and gene expression profiles were compared. [(14)C]-docetaxel and [(14)C]-cabazitaxel uptake assays in vitro and cytotoxicity assays were performed to validate direct involvement of transporter genes in taxane sensitivity. RESULTS: Organic anion-transporting polypeptide (SLCO1B3), an influx transporter of docetaxel, was significantly downregulated in PC346C-DOC tumours. In accordance with this finding, intratumoural concentrations of docetaxel and cabazitaxel were significantly decreased in PC346C-DOC as compared with levels in chemotherapy-naive PC346C tumours. In addition, silencing of SLCO1B3 in chemo-naive PC346C resulted in a two-fold decrease in intracellular concentrations of both taxanes. Overexpression of SLCO1B3 showed higher sensitivity to docetaxel and cabazitaxel. CONCLUSIONS: The SLCO1B3 determines intracellular concentrations of docetaxel and cabazitaxel and consequently influences taxane efficacy. Loss of the drug transporter SLCO1B3 may drive taxane resistance in prostate cancer.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/pharmacology , Drug Resistance, Neoplasm/physiology , Neoplasm Proteins/physiology , Organic Anion Transporters, Sodium-Independent/physiology , Prostatic Neoplasms/drug therapy , Taxoids/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Androgens , Androstenes/pharmacology , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Antineoplastic Agents, Phytogenic/therapeutic use , Benzamides , Biological Transport , Cell Line, Tumor , Docetaxel , Drug Resistance, Multiple/genetics , Drug Resistance, Multiple/physiology , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Heterografts , Humans , Male , Mice, Nude , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology , Nitriles , Organic Anion Transporters, Sodium-Independent/biosynthesis , Organic Anion Transporters, Sodium-Independent/genetics , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA Interference , RNA, Small Interfering/pharmacology , Solute Carrier Organic Anion Transporter Family Member 1B3 , Taxoids/pharmacokinetics , Taxoids/therapeutic use
3.
Prostate ; 76(10): 927-36, 2016 07.
Article in English | MEDLINE | ID: mdl-26997363

ABSTRACT

BACKGROUND: Resistance to docetaxel is common in metastatic castration-resistant prostate cancer (mCRPC) and may be caused by sub-therapeutic intratumoral drug concentrations. Cabazitaxel demonstrated survival benefit in docetaxel-pretreated and docetaxel-refractory patients. In this study, we investigated whether the superior antitumor activity of cabazitaxel in mCRPC is explained by higher intratumoral cabazitaxel levels. Since recent studies suggest a reduced efficacy of docetaxel following treatment with novel androgen receptor (AR)-targeted agents, we also investigated taxane efficacy in an enzalutamide-resistant tumor model. METHODS: Intratumoral concentrations of docetaxel and cabazitaxel were correlated with antitumor activity in docetaxel-naïve, docetaxel-resistant, and enzalutamide-resistant patient-derived xenografts (PDXs) of prostate cancer. RESULTS: Intratumoral drug levels were negatively related to intrinsic and acquired resistance to docetaxel. Also, the observed stronger antitumor activity of cabazitaxel was associated with increased cumulative exposure and higher intratumoral of cabazitaxel concentrations in all PDXs. CONCLUSIONS: The superior antitumor activity of cabazitaxel in docetaxel- and enzalutamide-resistant tumors can be partly attributed to higher intratumoral drug concentrations. Especially for patients who are intrinsically resistant to docetaxel resulting from suboptimal intratumoral docetaxel concentrations, cabazitaxel may be the preferred chemotherapeutic agent. Prostate 76:927-936, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Prostatic Neoplasms, Castration-Resistant/diet therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Taxoids/pharmacokinetics , Taxoids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Benzamides , Docetaxel , Drug Resistance, Neoplasm , Humans , Immunohistochemistry , Male , Mice , Mice, Nude , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/analysis , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/chemistry , Receptors, Androgen/drug effects , Taxoids/analysis , Xenograft Model Antitumor Assays
4.
Mol Pharmacol ; 88(3): 477-87, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26108972

ABSTRACT

The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy-dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH4Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression.


Subject(s)
Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Lysosomes/metabolism , Piperazines/pharmacology , Pyrimidines/pharmacology , Amantadine/pharmacology , Ammonium Chloride/pharmacology , Apoptosis , Cell Cycle , Cell Line, Tumor , HEK293 Cells , Humans , Imatinib Mesylate , Lysosomes/drug effects , Macrolides/pharmacology , Organic Cation Transporter 1/metabolism , Prazosin/pharmacology
5.
Breast Cancer Res Treat ; 152(1): 119-128, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26050156

ABSTRACT

The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacokinetics , Breast Neoplasms/drug therapy , Breast Neoplasms/physiopathology , Circadian Rhythm , Selective Estrogen Receptor Modulators/pharmacokinetics , Tamoxifen/pharmacokinetics , Adult , Animals , Breast Neoplasms/genetics , Cross-Over Studies , Cytochrome P-450 Enzyme System/genetics , Disease Models, Animal , Female , Humans , Mice , Middle Aged , Pharmacogenetics
6.
Clin Pharmacokinet ; 54(8): 851-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25647628

ABSTRACT

BACKGROUND AND OBJECTIVE: Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation. METHODS: We performed studies in male FVB-mice aged 8-12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration-time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times. RESULTS: Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14-27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (C trough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (C trough-1 p.m. 66.0 ng/mL; C trough-6 p.m. 58.9 ng/mL; C trough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times. CONCLUSIONS: Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower C trough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.


Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Indoles/administration & dosage , Indoles/pharmacokinetics , Neoplasms/drug therapy , Neoplasms/metabolism , Pyrroles/administration & dosage , Pyrroles/pharmacokinetics , Administration, Oral , Aged , Animals , Antineoplastic Agents/blood , Chronotherapy/methods , Circadian Rhythm/physiology , Cross-Over Studies , Drug Evaluation, Preclinical , Female , Humans , Indoles/blood , Male , Mice , Middle Aged , Neoplasms/blood , Prospective Studies , Pyrroles/blood , Sunitinib
7.
Clin Cancer Res ; 20(18): 4776-83, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25024258

ABSTRACT

PURPOSE: RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of this new drug. EXPERIMENTAL DESIGN: Sequential cohorts of 3 to 6 patients were treated per dose level. Blood, urine samples, and skin biopsies for full PK and/or PD analyses were collected. RESULTS: Twenty-six patients were enrolled in 6-dose levels from 10 to 160 mg/d. Four dose-limiting toxicities were observed in 2 of the 6 patients enrolled at the highest dose level. These toxicities were AST/ALT elevations in 1 patient, paroxysmal supraventricular tachycardias (SVTs), hypotension, and an increase in troponin T in another patient. The plasma PK of RGB-286638 was shown to be linear over the studied doses. The interpatient variability in clearance was moderate (variation coefficient 7%-36%). The PD analyses in peripheral blood mononuclear cells, serum (apoptosis induction) and skin biopsies (Rb, p-Rb, Ki-67, and p27(KIP1) expression) did not demonstrate a consistent modulation of mechanism-related biomarkers with the exception of lowered Ki-67 levels at the MTD level. The recommended MTD for phase II studies is 120 mg/d. CONCLUSIONS: RGB-286638 is tolerated when administered at 120 mg/d for 5 days every 28 days. Prolonged disease stabilization (range, 2-14 months) was seen across different dose levels.


Subject(s)
Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Urea/analogs & derivatives , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Cyclin-Dependent Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Urea/administration & dosage , Urea/adverse effects , Urea/pharmacokinetics
8.
Clin Cancer Res ; 19(22): 6296-304, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-23983259

ABSTRACT

PURPOSE: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m(2) were explored. RESULTS: Forty patients [24M/16F, median age 61 years (45-79)] were enrolled. At 4.5 mg/m(2), dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m(2), DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m(2), one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m(2). No complete or partial responses during treatment were observed; one patient at 4.0 mg/m(2) had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. CONCLUSION: The MTD for E7107 using this schedule is 4.0 mg/m(2). Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Epoxy Compounds/therapeutic use , Macrolides/therapeutic use , Neoplasms/drug therapy , Spliceosomes/drug effects , Aged , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/pharmacokinetics , Apoptosis/drug effects , Drug Administration Schedule , Epoxy Compounds/adverse effects , Epoxy Compounds/pharmacokinetics , Female , Humans , Leukocytes, Mononuclear/drug effects , M Phase Cell Cycle Checkpoints/drug effects , Macrolides/adverse effects , Macrolides/pharmacokinetics , Male , Maximum Tolerated Dose , Middle Aged , RNA, Messenger/biosynthesis , Spliceosomes/metabolism , Treatment Outcome
10.
Invest New Drugs ; 31(2): 399-408, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23161335

ABSTRACT

BACKGROUND: A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. METHODS: Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. RESULTS: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. CONCLUSION: Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study.


Subject(s)
Lymphoma, B-Cell/drug therapy , Neoplasms/drug therapy , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Afatinib , Aged , Aged, 80 and over , Cohort Studies , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Prognosis , Tissue Distribution
11.
Clin Cancer Res ; 17(22): 7156-63, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21976547

ABSTRACT

PURPOSE: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor. EXPERIMENTAL DESIGN: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors. RESULTS: Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors. CONCLUSION: Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.


Subject(s)
Phenylurea Compounds/administration & dosage , Quinolines/administration & dosage , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Adult , Aged , Antineoplastic Agents/administration & dosage , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/drug therapy , Phenylurea Compounds/adverse effects , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Quinolines/adverse effects , Quinolines/pharmacokinetics , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-3/antagonists & inhibitors
12.
Drug Resist Updat ; 14(1): 22-34, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21251871

ABSTRACT

Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters (OCTs)--and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Organic Cation Transport Proteins/metabolism , Organoplatinum Compounds/pharmacokinetics , Animals , Antineoplastic Agents/pharmacology , Biological Transport , Carboplatin/pharmacokinetics , Carboplatin/pharmacology , Cisplatin/pharmacokinetics , Cisplatin/pharmacology , Drug Interactions , Drug Resistance, Neoplasm , Humans , Organoplatinum Compounds/pharmacology , Oxaliplatin
13.
Clin Cancer Res ; 17(3): 406-15, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21163869

ABSTRACT

Imatinib mesylate is approved for the treatment of chronic myeloid leukemia (CML) and advanced gastrointestinal stromal tumors (GIST). Unfortunately, in the course of treatment, disease progression occurs in the majority of patients with GIST. Lowered plasma trough levels of imatinib over time potentially cause disease progression, a phenomenon known as "acquired pharmacokinetic drug resistance." This outcome may be the result of an altered expression pattern or activity of drug transporters. To date, the role of both efflux transporters (ATP-binding cassette transporters, such as ABCB1 and ABCG2) and uptake transporters [solute carriers such as organic cation transporter 1 (OCT1) and organic anion transporting polypeptide 1A2 (OATP1A2)] in imatinib pharmacokinetics and pharmacodynamics has been studied. In vitro experiments show a significant role of ABCB1 and ABCG2 in cellular uptake and retention of imatinib, although pharmacokinetic and pharmacogenetic data are still scarce and contradictory. ABCB1 and ABCC1 expression was shown in GIST, whereas ABCB1, ABCG2, and OCT1 were found in mononuclear cells in CML patients. Several studies have reported a clinical relevance of tumor expression or activity of OCT1 in CML patients. Further (clinical) studies are required to quantify drug transporter expression over time in organs involved in imatinib metabolism, as well as in tumor tissue. In addition, more pharmacogenetic studies will be needed to validate associations.


Subject(s)
Gastrointestinal Stromal Tumors/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Membrane Transport Proteins/metabolism , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Benzamides , Drug Resistance, Neoplasm , Humans , Imatinib Mesylate , Piperazines/pharmacology , Pyrimidines/pharmacology
14.
Eur J Cancer ; 46(16): 3016-21, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20801016

ABSTRACT

PURPOSE: To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers. PATIENTS AND METHODS: Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1 h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3-6 patients were treated at each dose level until MTD was reached. RESULTS: Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2 h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120 mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24 h after administration. Investigated plasma biomarkers sPLA(2) and SC5b-9 were related to, but not predictive for, acute infusion reactions. CONCLUSION: The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development.


Subject(s)
Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Liposomes , Male , Maximum Tolerated Dose , Middle Aged
15.
Clin Cancer Res ; 14(10): 3141-8, 2008 May 15.
Article in English | MEDLINE | ID: mdl-18483382

ABSTRACT

PURPOSE: The activity of imatinib in leukemia has recently been linked with expression of the organic cation transporter 1 (OCT1) gene SLC22A1. Here, we characterized the contribution of solute carriers to imatinib transport in an effort to further understand mechanisms involved in the intracellular uptake and retention (IUR) of the drug. EXPERIMENTAL DESIGN: IUR of [3H]imatinib was studied in Xenopus laevis oocytes and HEK293 cells expressing OATP1A2, OATP1B1, OATP1B3, OCT1-3, OCTN1-2, or OAT1-3. Gene expression was determined in nine leukemia cell lines using the Affymetrix U133 array. RESULTS: Imatinib was not found to be a substrate for OCT1 in oocytes (P = 0.21), whereas in HEK293 cells IUR was increased by only 1.20-fold relative to control cells (P = 0.002). Furthermore, in 74 cancer patients, the oral clearance of imatinib was not significantly altered in individuals carrying reduced-function variants in SLC22A1 (P = 0.99). Microarray analysis indicated that SLC22A1 was interrelated with gene expression of various transporters, including ABCB1, ABCC4, ABCG2 (negative), and OATP1A2 (positive). Imatinib was confirmed to be a substrate for the three efflux transporters (P < 0.05) as well as for OATP1A2 (P = 0.0001). CONCLUSIONS: This study suggests that SLC22A1 expression is a composite surrogate for expression of various transporters relevant to imatinib IUR. This observation provides a mechanistic explanation for previous studies that have linked SLC22A1 with the antitumor activity of imatinib. Because of its high expression in the intestine, ciliary body, gliomas, and leukemia cells, OATP1A2 may play a key role in imatinib pharmacokinetics-pharmacodynamics.


Subject(s)
Antineoplastic Agents/metabolism , Drug Resistance, Neoplasm/genetics , Gastrointestinal Stromal Tumors/genetics , Organic Cation Transporter 1/genetics , Piperazines/metabolism , Pyrimidines/metabolism , Animals , Benzamides , Cell Line, Tumor , Gastrointestinal Stromal Tumors/drug therapy , Gene Expression , Humans , Imatinib Mesylate , Organic Cation Transporter 1/metabolism , Polymerase Chain Reaction , Xenopus laevis
16.
Rev. peru. biol. (Impr.) ; 14(1): 139-144, ago. 2007. ilus, tab
Article in Spanish | LIPECS | ID: biblio-1111153

ABSTRACT

Este estudio se realizó en la laguna El Paraíso, departamento de Lima, Perú, de abril de 1999 a abril del 2000. Tuvo como objetivos la determinación de la diversidad específica en aves; la densidad poblacional de las principales familias de uso cinegético y la determinación de los microhábitats más importantes para los grupos evaluados. Se reportaron 81 especies de aves las cuales pertenecen a 62 géneros y a 35 familias. En esta cifra se reportan 19 especies nuevas para el área de Paraíso; el 46% de la diversidad de aves está dada por las familias Scolopacidae (14%), Ardeidae (10%), Laridae (7%), Anatidae (5%), Charadriidae (5%) y Columbidae (5%). La familia Rallidae es la más abundante y está representada por dos especies Gallinula chloropus "polla de agua" y Fulica ardesiaca "gallareta", siendo la primera más numerosa. Asimismo, se dan las recomendaciones para la conservación del área.


This study was carried out at El Paraíso lagoon, Lima, Peru, from April 1999 to April 2000. The main goals was determinated the birds specific diversity, the population density of main cinegetic bird families and the determination of the most important microhabitats for the studied groups. 81 birds species (19 species are new for the area) were reported, distribuited in 62 generas and 35 families. 46% of the diversity is given for the following families: Scolopacidae (14%), Ardeidae (10%), Laridae (7%), Anatidae (5%), Charadriidae (5%) and Columbidae (5%). The Rallidae family is the most abundant and is represented for two species Gallinula chloropus "Common Moorhen" y Fulica ardesiaca "Slate-colored Coot". It is given recommendations for the conservation of the area.


Subject(s)
Animals , Birds/immunology , Coastal Lagoon
17.
Clin Pharmacol Ther ; 80(2): 192-201, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16890580

ABSTRACT

OBJECTIVE: Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib. METHODS: Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism-based techniques. RESULTS: Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies. CONCLUSIONS: This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.


Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Pharmaceutical Preparations/metabolism , Piperazines/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacokinetics , ATP-Binding Cassette Transporters/genetics , Adult , Aged , Aged, 80 and over , Alleles , Benzamides , Biological Transport, Active , Cell Line, Tumor , Cohort Studies , Cytochrome P-450 Enzyme System/genetics , Female , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/metabolism , Gene Frequency , Genotype , Humans , Imatinib Mesylate , Isoenzymes/genetics , Male , Middle Aged , Phenotype , Proto-Oncogene Proteins c-kit/genetics , Stromal Cells/metabolism
18.
Cancer Biol Ther ; 5(8): 943-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16775422

ABSTRACT

The effectiveness of platinum drugs in the treatment of cancer is hindered by intrinsic and acquired resistance. The cause of clinical resistance to platinum compounds is still unknown. In an attempt to identify new cellular mechanisms of cisplatin resistance, a one-step cisplatin-selection procedure was used to generate resistant sublines of the platinum sensitive A2780 ovarian cancer cell line. In the present study we selected an A2780 subline, A2780-Pt, that has a significantly reduced ability to accumulate cisplatin (36% of the parent A2780 cell line) and consequently shows a clear cisplatin-resistant phenotype (resistance factor, i.e., RF: 8.6). The A2780-Pt cell line was specifically cross-resistant to carboplatin (RF: 12.0), tetraplatin (RF: 8.1) and oxaliplatin (RF: 6.1) which was associated with a reduced cellular platinum accumulation (50%, 54% and 58% of A2780, respectively). No cross-resistance was found for a variety of other anticancer agents. Further experiments to determine the cause of the platinum resistance of the A2780-Pt cell line revealed that: (1) impaired cellular platinum accumulation could not be attributed to aberrant expression of MRP2 (ABCC2), CTR1 (SLC31A1), ATP7A or ATP7B, (2) resistance was not associated with platinum inactivation by metallothionein and glutathione, (3) the platinum efflux rate was similar to that of A2780, (4) the defect in cellular accumulation and the resistance could be overcome by treatment with cisplatin nanocapsules, consistent with impaired influx, and (5) the defect in accumulation is specific for platinum compounds in the cis-configuration, since A2780-Pt cells did not show reduced accumulation of transplatin. This specificity suggests that not passive diffusion but an inward transporter is impaired in A2780-Pt. In conclusion, we generated an A2780 subline that showed a uniquely stable platinum resistance phenotype, which could theoretically be caused by an impaired inward transporter specific for cis-configurated platinum compounds.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Cation Transport Proteins/physiology , Cisplatin/pharmacokinetics , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Carboplatin/pharmacokinetics , Female , Glutathione/metabolism , Humans , Multidrug Resistance-Associated Protein 2 , Nanotechnology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Organoplatinum Compounds/pharmacokinetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Oxaliplatin , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism
19.
Bol. Lima ; 28(143): 28-37, 2006.
Article in Spanish | LIPECS | ID: biblio-1106906

ABSTRACT

In this study, some biotic communities of the Lurin River estuary are presented. In it are reported snails (hosts of Fasciola hepatica) and bacteria of medical importance, Vibrio Cholerae specifically. Furthermore, the condition of the ecosytem and its potential function as a reservoir of human infections, are discussed.


Se presenta un estudio ecológico sobre algunas comunidades bióticas de la desembocadura el río Lurín, registrándose la presencia de caracoles que son hospedadores intermediarios de Fasciola hepatica y bacterias de importancia médica, específicamente Vidrio Cholerae. Se discute el estado del ecosistema y su rol como potencial fuente de de infecciones para el hombre. Asimismo el presente trabajo contribuye a conocimiento de la ornitofauna acuática, la cual se interrelaciona con el ciclo biológico del microorganismo.


Subject(s)
Birds , Snails , Ecological Studies , Estuaries , Fasciola hepatica , Vibrio cholerae , Peru , Zooplankton
20.
Cancer Biol Ther ; 4(11): 1270-4, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16294026

ABSTRACT

Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRalpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRalpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRalpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRalpha exon 12, 142 PDGFRalpha exon18, 17 PDGFRbeta exon 12 and 17 PDGFRbeta exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRalpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.


Subject(s)
Antineoplastic Agents/pharmacology , Gastrointestinal Stromal Tumors/genetics , Mutation , Piperazines/pharmacology , Proto-Oncogene Proteins c-kit/genetics , Pyrimidines/pharmacology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Benzamides , DNA Mutational Analysis , Enzyme Activation/genetics , Gastrointestinal Stromal Tumors/pathology , Humans , Imatinib Mesylate , Proto-Oncogene Proteins c-kit/metabolism , Receptor, Platelet-Derived Growth Factor alpha/metabolism
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