RESUMO
Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Terapia de Salvação , Resultado do TratamentoRESUMO
In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Resultado do TratamentoRESUMO
Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Compostos de Epóxi/metabolismo , Rim/patologia , Mitocôndrias/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Caspase 3/metabolismo , Linhagem Celular , Ativação Enzimática , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , SuínosRESUMO
Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.
Assuntos
Injúria Renal Aguda/prevenção & controle , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , NF-kappa B/metabolismo , Ácido 8,11,14-Eicosatrienoico/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/enzimologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/genética , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. METHODS AND RESULTS: Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1alpha, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. CONCLUSIONS: The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.
Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Aterosclerose/prevenção & controle , Dislipidemias/prevenção & controle , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Administração Oral , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Aterosclerose/enzimologia , Aterosclerose/patologia , Disponibilidade Biológica , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Dislipidemias/induzido quimicamente , Dislipidemias/enzimologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/metabolismo , Mediadores da Inflamação/sangue , Molécula 1 de Adesão Intercelular/genética , Interleucina-1alfa/sangue , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Ligadura , Masculino , Camundongos , Camundongos Knockout , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Inflamação/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-beta signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-beta-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-beta signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-beta-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-betaRI inhibitor may be useful in the treatment of glioblastoma.