RESUMO
The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an exâ vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses.
Assuntos
Inibidores da Angiogênese/química , Barbitúricos/química , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Barbitúricos/síntese química , Barbitúricos/farmacologia , Cristalografia por Raios X , Conformação Molecular , Ftalimidas/química , Ratos , Relação Estrutura-Atividade , Talidomida/químicaRESUMO
Thalidomide has demonstrated clinical activity in various malignancies affecting immunomodulatory and angiogenic pathways. The development of novel thalidomide analogs with improved efficacy and decreased toxicity is an ongoing research effort. We recently designed and synthesized a new class of compounds, consisting of both tetrafluorinated thalidomide analogues (Gu973 and Gu998) and tetrafluorobenzamides (Gu1029 and Gu992). In this study, we demonstrate the antiangiogenic properties of these newly synthesized compounds. We examined the specific antiangiogenic characteristics in vitro using rat aortic rings with carboxyamidotriazole as a positive control. In addition, further in vitro efficacy was evaluated using human umbilical vein endothelial cells (HUVEC) and PC3 cells treated with 5 and 10 µmol/L doses of each compound. All compounds were seen to reduce microvessel outgrowth in rat aortic rings as well as to inhibit HUVECs to a greater extent, at lower concentrations than previously tested thalidomide analogs. The antiangiogenic properties of the compounds were also examined in vivo in fli1:EGFP zebrafish embryos, where all compounds were seen to inhibit the extent of outgrowth of newly developing blood vessels. In addition, Gu1029 and Gu973 reduced the anti-inflammatory response in mpo:GFP zebrafish embryos, whereas Gu998 and Gu992 showed no difference. The compounds' antitumor effects were also explored in vivo using the human prostate cancer PC3 xenograft model. All four compounds were also screened in vivo in chicken embryos to investigate their teratogenic potential. This study establishes these novel thalidomide analogues as a promising immunomodulatory class with anticancer effects that warrant further development to characterize their mechanisms of action.
Assuntos
Inibidores da Angiogênese/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Neovascularização Patológica/prevenção & controle , Talidomida/análogos & derivados , Talidomida/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Concentração Inibidora 50 , Masculino , Ratos Sprague-Dawley , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
Nelfinavir is an HIV protease inhibitor being repurposed as an anti-cancer agent in preclinical models and in small oncology trials, yet the MTD of nelfinavir has not been determined. Therefore, we conducted a Phase Ia study to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of nelfinavir in subjects with advanced solid tumors. Adults with refractory cancers were given oral nelfinavir twice daily with pharmacokinetic and pharmacodynamic analyses. Twenty-eight subjects were enrolled. Nelfinavir was generally well tolerated. Common adverse events included diarrhea, anemia, and lymphopenia, which were mostly mild. The DLT was rapid-onset neutropenia that was reversible. The MTD was established at 3125 mg twice daily. In an expansion cohort at the MTD, one of 11 (9%) evaluable subjects had a confirmed partial response. This, plus two minor responses, occurred in subjects with neuroendocrine tumors of the midgut or pancreatic origin. Thirty-six percent of subjects had stable disease for more than 6 months. In peripheral blood mononuclear cells, Nelfinavir inhibited AKT and induced markers of ER stress. In summary, nelfinavir is well tolerated in cancer patients at doses 2.5 times the FDA-approved dose for HIV management and showed preliminary activity in tumors of neuroendocrine origin.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores da Protease de HIV/uso terapêutico , Nelfinavir/uso terapêutico , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Esquema de Medicação , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Masculino , Maryland , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nelfinavir/administração & dosagem , Nelfinavir/efeitos adversos , Nelfinavir/farmacocinética , Neoplasias/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity.
Assuntos
Inibidores da Angiogênese/química , Ftalimidas/química , Inibidores da Angiogênese/farmacologia , Compostos de Anilina/química , Animais , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Etanol/química , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Metanol/química , Neovascularização Fisiológica/efeitos dos fármacos , Ácidos Ftálicos/química , Ftalimidas/farmacologia , Ratos , Reprodutibilidade dos Testes , Solventes/química , Tecnologia Farmacêutica/métodos , Temperatura , Técnicas de Cultura de TecidosRESUMO
PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 µmol/L; K(i) = 11.7 µmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.
Assuntos
Benzenossulfonatos/farmacocinética , Glucuronosiltransferase/genética , Piridinas/farmacocinética , Idoso , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Área Sob a Curva , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/metabolismo , Bilirrubina/metabolismo , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Genótipo , Glucuronídeos/metabolismo , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Humanos , Hiperbilirrubinemia/induzido quimicamente , Hiperbilirrubinemia/genética , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Farmacogenética , Compostos de Fenilureia , Projetos Piloto , Polimorfismo Genético , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Piridinas/efeitos adversos , Piridinas/metabolismo , Sorafenibe , UDP-Glucuronosiltransferase 1ARESUMO
LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NCI60 cancer cell lines resulted in a mean GI50 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human umbilical vein endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 µM. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 µM. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCB1. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Administração Oral , Inibidores da Angiogênese/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab , Disponibilidade Biológica , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Ácidos Isonicotínicos/administração & dosagem , Masculino , Camundongos , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Paclitaxel/administração & dosagem , Permeabilidade , Ratos , Ratos Sprague-Dawley , Sulfonamidas/administração & dosagem , Fatores de Tempo , Moduladores de Tubulina/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Sorafenib is a multikinase inhibitor with activity against B-raf, C-raf, VEGFR2, PDGFRß and FGFR1. Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). The pharmacokinetics (PK) of sorafenib are highly variable between subjects. Sorafenib exposure increases less than dose proportionally (likely due to limited solubility). Sorafenib undergoes enterohepatic recycling (EHC). WHAT THIS STUDY ADDS: This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility-limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying. This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified. This model can be used to simulate and explore alternative dosing regimens and to develop exposure-response relationships for sorafenib. AIMS: To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib. METHODS: PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis. RESULTS: A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter-individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h(-1) (3.6-22.3 l h(-1) ), volume 213 l (50-1000 l), mean absorption transit time 1.98 h (0.5-13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h. CONCLUSIONS: Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.
Assuntos
Antineoplásicos/farmacocinética , Benzenossulfonatos/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Citocromo P-450 CYP3A/metabolismo , Feminino , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteínas Tirosina Quinases/metabolismo , Sorafenibe , Estatística como Assunto , UDP-Glucuronosiltransferase 1ARESUMO
PURPOSE: P-glycoprotein (Pgp) antagonists have been difficult to develop because of complex pharmacokinetic interactions and a failure to show meaningful results. Here we report the results of a pharmacokinetic and pharmacodynamic trial using a third-generation, potent, noncompetitive inhibitor of Pgp, tariquidar (XR9576), in combination with docetaxel. EXPERIMENTAL DESIGN: In the first treatment cycle, the pharmacokinetics of docetaxel (40 mg/m(2)) were evaluated after day 1 and day 8 doses, which were administered with or without tariquidar (150 mg). (99m)Tc-sestamibi scanning and CD56(+) mononuclear cell rhodamine efflux assays were conducted to assess Pgp inhibition. In subsequent cycles, 75 mg/m(2) docetaxel was administered with 150 mg tariquidar every 3 weeks. RESULTS: Forty-eight patients were enrolled onto the trial. Nonhematologic grade 3/4 toxicities in 235 cycles were minimal. Tariquidar inhibited Pgp-mediated rhodamine efflux from CD56(+) cells and reduced (99m)Tc-sestamibi clearance from the liver. There was striking variability in basal sestamibi uptake; a 12% to 24% increase in visible lesions was noted in 8 of 10 patients with lung cancer. No significant difference in docetaxel disposition was observed in pairwise comparison with and without tariquidar. Four partial responses (PR) were seen (4/48); 3 in the non-small cell lung cancer (NSCLC) cohort, measuring 40%, 57%, and 67% by RECIST, and 1 PR in a patient with ovarian cancer. CONCLUSIONS: Tariquidar is well tolerated, with less observed systemic pharmacokinetic interaction than previous Pgp antagonists. Variable effects of tariquidar on retention of sestamibi in imageable lung cancers suggest that follow-up studies assessing tumor drug uptake in this patient population would be worthwhile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Quinolinas/administração & dosagem , Taxoides/administração & dosagem , Neoplasias do Colo do Útero/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Quinolinas/farmacocinéticaRESUMO
PURPOSE: Although the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e., blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT prolongation and cardiotoxicity. EXPERIMENTAL DESIGN: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced heart rate-corrected QT interval (QTc) prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. RESULTS: Here, we show that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also show that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin. CONCLUSIONS: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT prolongation following the administration of ABCB1-substrate drugs.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Arritmias Cardíacas/induzido quimicamente , Miocárdio/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacocinética , Depsipeptídeos/farmacologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A simple, rapid and sensitive liquid chromatography/tandem mass spectrometric (LC/MS/MS) analytical method was developed for quantification of Hsp90 inhibitor PF-04928473 in human plasma, following administration of its prodrug, PF-04929113. Sample processing involved protein precipitation by addition of 0.4 mL of methanol containing internal standard (PF-04972487) to 50 µL volume of plasma sample. Chromatographic separation of PF-04928473 and PF-04972487 was achieved on a Phenomenex®) Luna C18(2) (2.0 mm x 50 mm, 5 µm) column using a gradient elution method with mobile phase solvents: methanol containing 0.1% formic acid and 0.1% formic acid at a flow rate of 0.25 mL/min. Detection was performed in electrospray positive ionization mode, monitoring the ion transitions from m/z 465.1â350.1 (PF-04928473) and m/z 447.0â329.1 (PF-04972487). The retention times for PF-04928473 and PF-04972487 were 1.86 and 2.85 min, respectively. Calibration curves were generated in the range of 2-2000 ng/mL. The accuracy and precision ranged from 94.1 to 99.0% and 86.7 to 97.6%, respectively, which were calculated using quality control samples of three different concentrations analyzed in quintuplicate on four different days.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Espectrometria de Massas em Tandem/métodos , Humanos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Romidepsin is a histone deacetylase inhibitor (HDI), approved by the US FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Although various mechanisms have been proposed for the activity of HDIs, including induction of genes controlling cell cycle, acetylation of cytoplasmic proteins and direct induction of apoptosis, the mechanism underlying activity of romidepsin and other HDIs in CTCL is not known. Romidepsin induces long-lasting responses. The side-effect profile is similar to that of other HDIs, causing fatigue, nausea and thrombocytopenia. Management of the CTCL population requires vigilence to prevent infection with skin contaminants, and monitoring of potassium and magnesium, electrolytes found to be low in a large proportion of patients. Electrocardiographic (ECG) changes are common but are not associated with myocardial damage. When molecular end points were evaluated in 61 patients enrolled on a Phase II trial with romidepsin, response was associated with persistence of acetylated histone H3, suggesting that drug exposure is important in effective therapy with romidepsin. Future studies will endeavor to identify combination strategies to increase the efficacy both in resistant CTCL and in solid tumors and to identify biomarkers of response that will allow selection of patients most likely to benefit from the therapy.
Assuntos
Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Doenças da Medula Óssea/induzido quimicamente , Ensaios Clínicos Fase II como Assunto , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacologia , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Marcação de Genes , Cardiopatias/induzido quimicamente , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/fisiologia , Humanos , Infecções/etiologia , Linfoma Cutâneo de Células T/enzimologia , Linfoma Cutâneo de Células T/patologia , Estrutura Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Neoplasias/enzimologia , Guias de Prática Clínica como AssuntoRESUMO
Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival and proliferation, as well as motility, making FAK a distinctive target in the field of anticancer drug development, especially with regards to metastatic disease.(1) Our objective was to demonstrate tumor growth inhibition by PF-562,271, a selective inhibitor of FAK and FAK2, or Pyk2,(2) in mouse xenograft models, both subcutaneous and metastatic, employing the human prostate cancer cell line PC3M-luc-C6, a modified PC3M cell line that expresses luciferase. After 2 weeks of treatment with PF-562,271, 25 mg/kg PO BID 5x/wk, the subcutaneous model showed a 62% tumor growth inhibition compared to control based on tumor measurements (p < 0.05), with a 88% vs. a 490% increase in bioluminescent signal for treatment and control respectively (p < 0.05). In the metastasis model, the percent change from baseline, after 18 days of treatment, of the treatment group was 2,854 vs. 14,190% for the vehicle (p < 0.01). These results show that PF-562,271 has a potent effect on metastatic prostate cancer growth in vivo.
Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Indóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Injeções Subcutâneas , Medições Luminescentes , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/enzimologia , Taxa de SobrevidaRESUMO
STUDY OBJECTIVE: To determine if excretion of sorafenib in sweat is associated with hand-foot skin reaction in patients receiving sorafenib. DESIGN: Prospective pilot study. SETTING: Outpatient clinic of a cancer research institution. PATIENTS: Two patients who were receiving sorafenib and developed a hand-foot skin reaction of at least grade 1 and two healthy subjects (controls). INTERVENTION: Sweat production was stimulated in both the patients with hand-foot skin reaction and the healthy subjects by means of pilocarpine iontophoresis. MEASUREMENTS AND MAIN RESULTS: Sweat samples were collected from the patients with hand-foot skin reaction and from the healthy subjects. Using liquid chromatography-tandem mass spectrometry, sorafenib concentrations were measured in the sweat samples. Sweat samples from the healthy subjects were spiked with known concentrations of sorafenib to determine the lower limit of quantification of the assay, which was determined to be 5 ng/ml. Sorafenib concentrations in the samples from the patients with hand-foot skin reaction were undetectable based on the assay's sensitivity. CONCLUSION: Our results suggest that hand-foot skin reaction in patients receiving sorafenib is not associated with excretion of sorafenib in sweat. Further studies are needed to understand the mechanism of hand-foot skin reaction, a treatment-limiting adverse effect of multikinase inhibitors.
Assuntos
Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Benzenossulfonatos/análise , Toxidermias/etiologia , Dermatoses do Pé/induzido quimicamente , Dermatoses da Mão/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Piridinas/análise , Suor/química , Antineoplásicos/análise , Antineoplásicos/sangue , Antineoplásicos/metabolismo , Benzenossulfonatos/sangue , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Iontoforese , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Pilocarpina/farmacologia , Projetos Piloto , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Piridinas/sangue , Índice de Gravidade de Doença , Sorafenibe , Espectrometria de Massas em TandemRESUMO
This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.
Assuntos
Proteínas de Membrana Transportadoras/fisiologia , Farmacogenética/métodos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/fisiologiaRESUMO
PURPOSE: UCN-01 potently inhibits protein kinase C, phosphatidylinositide-dependent kinase-1, and checkpoint kinase 1, which are involved in regulating cell cycle progression. We designed a phase I study to determine the maximum tolerated dose (MTD) of UCN-01 with prednisone in patients with advanced malignancies. METHODS: UCN-01 was administered as a continuous intravenous infusion over 72 h in cycle 1 and 36 h in subsequent cycles. Prednisone was given orally at 60 mg/m(2) per day for five consecutive days within each 28-day cycle. Standard dose escalation was employed, and MTD was defined as the dose at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Plasma pharmacokinetics of UCN-01 were assessed. RESULTS: Fifteen patients received a total of 55 courses of treatment. The MTD and the recommended phase II dose of UCN-01 in this combination is 72 mg/m(2) total dose over 72 h for cycle 1 followed by 36 mg/m(2) per cycle over 36 h. All patients experienced hyperglycemia but responded to insulin treatment. Hypophosphatemia was a DLT in two patients. There were no cumulative toxicities. No objective responses were observed, but five patients had stable disease, including two patients with lymphoid malignancies who had prolonged disease stabilizations. UCN-01 has a long terminal half-life and low clearance; there was wide inter-patient variability in peak concentrations. CONCLUSION: UCN-01 can be safely administered in combination with prednisone without unacceptable toxicity. The prolonged stable disease in two patients with lymphoid malignancies is a proof of principle for the evaluation of cyclin-dependent kinase inhibitors in oncology.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma/tratamento farmacológico , Linfoma/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/patologia , Prednisona/administração & dosagem , Estaurosporina/administração & dosagem , Estaurosporina/análogos & derivados , Estaurosporina/farmacocinética , Adulto JovemRESUMO
Romidepsin has shown promise in the treatment of T-cell lymphomas, and so we evaluated molecular endpoints gathered from 61 patients enrolled on a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma at the National Institutes of Health. The endpoints included histone H3 acetylation and ABCB1 gene expression in peripheral blood mononuclear cells (PBMCs); ABCB1 gene expression in tumour biopsy samples; and blood fetal haemoglobin levels (HbF), all of which were increased following romidepsin treatment. The fold increase in histone acetylation in PBMCs at 24 h was weakly to moderately well correlated with the pharmacokinetic parameters C(max) and area under the curve (AUC)(last) (rho = 0.37, P = 0.03 and rho = 0.36, P = 0.03 respectively) and inversely associated with clearance (rho = -0.44; P = 0.03). Histone acetylation in PBMCs at 24 h was associated with response (P = 0.026) as was the increase in fetal haemoglobin (P = 0.014); this latter association may be due to the longer on-study duration for patients with disease response. Together, these results suggest that pharmacokinetics may be an important determinant of response to histone deacetylase inhibitors (HDIs) - the association with histone acetylation in PBMCs at 24 h is consistent with a hypothesis that potent HDIs are needed for a critical threshold of drug exposure and durable activity.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Acetilação , Biópsia , Hemoglobina Fetal/análise , Histonas/metabolismo , Humanos , Immunoblotting , Leucócitos Mononucleares/metabolismo , Linfoma de Células T/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/metabolismoRESUMO
PURPOSE: Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer. EXPERIMENTAL DESIGN: 17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs). RESULTS: A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable. CONCLUSION: Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
Assuntos
Antineoplásicos/administração & dosagem , Benzoquinonas/administração & dosagem , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Benzoquinonas/efeitos adversos , Benzoquinonas/farmacocinética , Esquema de Medicação , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Infusões Intravenosas , Lactamas Macrocíclicas/efeitos adversos , Lactamas Macrocíclicas/farmacocinética , Leucócitos Mononucleares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.
Assuntos
Depsipeptídeos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Área Sob a Curva , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacocinética , Fadiga/induzido quimicamente , Feminino , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Leucemia/induzido quimicamente , Linfoma Cutâneo de Células T/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Trombocitopenia/induzido quimicamente , Resultado do TratamentoRESUMO
Thalidomide is emerging as a potentially important therapeutic option in the treatment of metastatic prostate cancer. Although the mechanism of action of this agent remains elusive in malignancies of the prostate, recent data has indicated that thalidomide may play a role in inflammation, immunomodulation, and anti-angiogenesis. Lenalidomide (CC-5013), a thalidomide analogue with improved activity and safety profile in certain disease contexts, is in the early stages of development in prostate cancer. This review will provide the current status of the history, mechanism, metabolism, and clinical use of thalidomide in metastatic prostate cancer. It will also describe the mechanism and clinical use of lenalidomide as it pertains to malignancies of the prostate.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Animais , Antineoplásicos/química , Humanos , Lenalidomida , Masculino , Neoplasias da Próstata/metabolismo , Talidomida/química , Resultado do TratamentoRESUMO
BACKGROUND: Imatinib, a tyrosine kinase inhibitor currently approved for treatment of several malignancies, has been shown to be a substrate for multiple efflux-transporter proteins, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP). The effect of inhibiting these transporters on tissue exposure to imatinib remains unclear. OBJECTIVE: To assess the role of these transporters on drug disposition, 50 mg/kg imatinib was administered to Balb/C mice, 30 minutes after receiving tariquidar (10 mg/kg), an inhibitor of both ABCB1 and ABCG2, or vehicle, via oral gavage. METHODS: Quantitative determination of imatinib in mouse plasma, liver and brain was performed using a newly-developed and validated liquid-chromatography-mass spectrometric method. RESULTS: Exposure to imatinib was 2.2-fold higher in plasma, liver and brain in mice that received tariquidar, as compared to those that received the vehicle (P = 0.001). The peak plasma concentration did not increase substantially, suggesting that tariquidar is affecting the distribution, metabolism and/or excretion of imatinib, rather than absorption. Though tariquidar increased the absolute exposure of imatinib, the brain-to-plasma ratio of imatinib was unaffected. CONCLUSION: This study suggests that intentional inhibition of ABCB1 and ABCG2 function at the blood-brain barrier is unlikely to significantly improve clinical outcome of imatinib with currently used dosing regimens.