RESUMEN
The aim of the present study was to assess the pharmacokinetics (PK) of metronomic capecitabine and its metabolites in a population of refractory metastatic colorectal cancer (mCRC) patients. Thirty-four patients (M/F, 22/12) with a diagnosis of mCRC received capecitabine 800 mg p.o. twice a day and cyclophosphamide 50 mg/day p.o. Blood samples were collected at baseline, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h and 5 h at day 1 after capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured by high performance liquid chromatography and the main PK parameters were calculated. Maximum plasma concentrations (Cmax) of capecitabine (11.51 ± 9.73 µg/ml) occurred at 0.5 h, whereas the Cmax of 5'-deoxy-5-fluorocytidine (5'-DFCR; 2.45 ± 2.93 µg/ml), 5'-deoxy-5-fluorouridine (5'-DFUR; 6.43 ± 8.2 µg/ml), and 5-fluorouracil (5-FU; 0.24 ± 0.16 µg/ml) were found at 1 h, 1.5 h and 1 h, respectively. Capecitabine, 5'-DFCR, 5'-DFUR and 5-FU AUCs at day 1 were 21.30 ± 10.78, 5.2 ± 4.6, 19.59 ± 3.83 and 0.66 ± 0.77 hxµg/ml, respectively. In conclusion, low doses of capecitabine were rapidly absorbed and extensively metabolized, achieving measurable plasma concentrations in a heavily pretreated population of patients.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina/farmacocinética , Capecitabina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Cromatografía Líquida de Alta Presión/métodos , Neoplasias Colorrectales/sangre , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Femenino , Floxuridina/farmacocinética , Floxuridina/uso terapéutico , Fluorouracilo/farmacocinética , Fluorouracilo/uso terapéutico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92 % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA. Plasma VNR was detected using a LC-MS-MS system. The fraction of patients free of progression, defined by criteria of the Prostate Cancer Clinical Trials Working Group 2, at 3 months was 61 %. PSA decrease ≥50 % from baseline was observed in 35 % of patients. Median PFS and OS were 4 months (95 % CI, 2.8-6.9) and 17.5 months (95 % CI, 10.8-24.5), respectively. Toxicity was mild, and no grade 4 toxicities were found. The mean plasma VNR Cmax ranged from 1 to 2.7 ng/ml (Tmax 1.1 h) and no evidence of drug accumulation was found. A moderate relationship was found between plasma sB7-H3 and PSA values (r = 0.565; P = 0.0094) at the baseline. Increased PFS (11.3 vs. 2.8 months; P = 0.0298) was observed in patients with sB7-H3 levels <30.25 ng/mL. Plasma VEGF AUC0-24day increased in non-responders (P < 0.0001), whereas responders maintained higher plasma TSP-1 AUC0-24day (P = 0.0063). In conclusion, metronomic VNR plus DEX showed favourable activity, and a low toxicity profile, in mCRPC patients. Plasma sB7-H3, VEGF and TSP-1 levels are potential pharmacodynamic markers at the reached low plasma concentrations of vinorelbine metronomically administered.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Óseas/secundario , Dexametasona/administración & dosificación , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/patología , Tasa de Supervivencia , Distribución Tisular , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , VinorelbinaRESUMEN
BACKGROUND: Docetaxel plus prednisone is currently the standard first-line treatment in metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to assess the clinical activity and pharmacodynamic/pharmacogenetic profile of docetaxel plus prednisone in combination with metronomic cyclophosphamide in mCRPC patients. METHODS: Forty-one chemotherapy-naive patients received docetaxel (60 mg/m(2) intravenously every 3 weeks up to 12 cycles) and, from day 2, prednisone 10 mg/day, celecoxib 400 mg/day, and metronomic cyclophosphamide 50 mg/day, continuously. Plasma VEGF and bFGF were detected by ELISA. Real-time PCR-SNP analysis of VEGF gene was performed using an ABI PRISM 7900HT SDS and TaqMan SNP genotyping. RESULTS: Eighty-seven percent of patients were free of progression at 6 months. A decrease in prostate-specific antigen ≥50% was observed in 82% of 39 evaluable patients, with a median time to progression of 12.3 months. Grade 3 adverse events were neutropenia (5%), thrombocytopenia, diarrhea, and stomatitis (2.5%). Median PFS and OS were 14.9 months (95% CI, 9.2-15.3 months) and 33.3 months (95% CI, 23-35.6 months), respectively. Of 11 patients (28%) with evaluable disease, 5 (44%) achieved a complete response, 2 (11%) a partial response, and 2 (11%) stable disease, whereas 2 showed disease progression. The -1154A/G VEGF polymorphism, plasma VEGF, and bFGF after the first cycle of chemotherapy may represent useful pharmacodynamic markers to predict better outcomes. CONCLUSIONS: The combination of docetaxel and oral metronomic chemotherapy is effective and well tolerated in mCRPC patients and may deserve further evaluation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/administración & dosificación , Ciclofosfamida/farmacocinética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Taxoides/administración & dosificación , Taxoides/farmacocinética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Administración Metronómica , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Progresión de la Enfermedad , Docetaxel , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/patología , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
AIMS: To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies. METHODS: Thirty-eight patients received 500 mg/mq(2) CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH(2), GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed. RESULTS: Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2-7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6-3.9 ms) and 7.1 ms (95% CI, 4.3-9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and C(max) values greater than 1.313 h × µg/ml and 0.501 µg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients. CONCLUSION: Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/farmacocinética , Neoplasias Gastrointestinales/tratamiento farmacológico , Pirazoles/farmacocinética , Sulfonamidas/farmacocinética , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Celecoxib , Ciclofosfamida/administración & dosificación , Femenino , Neoplasias Gastrointestinales/sangre , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Tegafur/administración & dosificación , Tegafur/farmacocinética , Uracilo/administración & dosificación , Uracilo/farmacocinética , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
In this prospective, case-control genetic study, 120 consecutive neovascular age-related macular degeneration (AMD) cases and 78 controls were enrolled. Two SNPs (rs2071559 and rs1870377) of VEGF-A receptor-2 (VEGFR-2) gene were analyzed with the technique of Real-Time PCR to investigate a genetic link between AMD and VEGFR-2 gene polymorphisms in Italian patients. The frequency of the VEGFR-2 genotype rs2071559 AA was significantly lower (18.33%) in patients with AMD than in the control subjects (34.62%; P = 0.0095, chi-square test; P(corr) = 0.038; OR = 0.42, 95% CI 0.22 to 0.82). In conclusion, although with the limitations of a small sample size and the few SNPs studied, this study demonstrates a lower frequency of VEGFR-2 rs2071559 AA genotype in an AMD patient population, suggesting future studies on the role VEGFR-2 SNPs.
Asunto(s)
Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Degeneración Macular Húmeda/genética , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The aim of the study was to evaluate the effects and the related pharmacological mechanisms of switched schedules of antiangiogenic and chemotherapeutic drugs beyond progression after a first-line treatment in a colorectal cancer preclinical model. In vivo studies were performed in nude mice subcutaneously transplanted with colon cancer cells. The treatments included drug combinations with a switch between chemotherapeutic (i.e., irinotecan and 5-fluorouracil) and/or antiangiogenic drugs (i.e., anti-VEGF antibodies and sunitinib) at the time of tumor progression. Proliferation assays were also achieved in vitro on different colon cancer cell lines exposed to SN-38 and sunitinib alone or in combination. ABCG2 gene expression was performed with real-time PCR and SN-38 intracellular concentrations were measured. The switch in the combined treatments, at the time of tumor progression, of the chemotherapeutic (from irinotecan to 5-fluoruracil), or the antiangiogenic drug (from anti-VEGF antibodies to sunitinib) or of both drugs induced a new response. Immunohistochemistry of stromal PDGF-C, PlGF, SD1-α, Tie-2, and VEGFR-2 showed statistical differences between tumors at the time of relapse and after the switched therapy. Moreover, the combination of SN-38 and sunitinib caused synergism on colon cancer cells, with significant inhibition of the ABCG2 gene expression and an increase of SN-38 intracellular concentrations. Our observations may be of clinical relevance, suggesting the switch of single chemotherapeutic or antiangiogenic drugs beyond progression of the disease to obtain a new tumor response due to a modulation of angiogenic factors and a direct effect on tumor cells with a possible variation of intracellular drug concentrations.
Asunto(s)
Inductores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/administración & dosificación , Antineoplásicos/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Progresión de la Enfermedad , Inductores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacocinética , Animales , Antineoplásicos/farmacocinética , Células CACO-2 , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación Preclínica de Medicamentos/métodos , Células HCT116 , Células HT29 , Humanos , Masculino , Ratones , Ratones DesnudosRESUMEN
The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATCcell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 µM) was tested by WST1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dosedependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGFA expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation.
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Antineoplásicos/administración & dosificación , Piperidinas/administración & dosificación , Quinazolinas/administración & dosificación , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/metabolismo , Relación Dosis-Respuesta a Droga , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Técnicas In Vitro , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinas/farmacología , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoAsunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Administración Metronómica , Animales , Antineoplásicos/administración & dosificación , Modelos Animales de Enfermedad , Perros , Metástasis de la Neoplasia , Neoplasias/sangre , Proyectos Piloto , Calidad de Vida , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
The identification of new therapeutic strategies is urgently needed for the management of patients affected by anaplastic thyroid cancer (ATC) due to their short survival and poor prognosis. Aim of the study was to determine the activity of the combination irinotecan/sunitinib on ATC cell growth in vitro and the antitumor effects in vivo. Proliferation assays were performed for 72 h on ATC cell lines exposed to the combination of SN-38, the active metabolite of irinotecan, and sunitinib. The simultaneous combination of sunitinib and SN-38, quantified by the combination index, determined a high synergism on ATC cells, increasing the intracellular concentrations of SN-38. Moreover, the synergistic combination greatly decreases the gene expression and the protein levels of vascular endothelial growth factor, colony stimulating factor 1 and ATP-binding cassette transporter G2 in ATC cells. A significant in vivo antitumor effect was observed in ATC xenografts with the simultaneous combination of irinotecan and sunitinib if compared to monotherapy. The simultaneous combination of irinotecan and sunitinib, in vitro and in vivo demonstrated a significant, synergistic ATC antitumor activity, suggesting a possible and rapid translation of this schedule into the clinics.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/análogos & derivados , Indoles/farmacología , Pirroles/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Anciano , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Camptotecina/administración & dosificación , Camptotecina/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Humanos , Indoles/administración & dosificación , Irinotecán , Masculino , Ratones , Ratones Desnudos , Pirroles/administración & dosificación , SunitinibRESUMEN
(NH3)2Pt(triacid) and (PPh3)2Pt(dehydrocholate)2 are novel bile acid-conjugated platinum complexes administered by oral route. The aims of the present study were to evaluate their in vitro cytotoxic activities on rat hepatoma cell line N1-S1, the in vivo antitumour effects in a syngeneic and orthotopic rat hepatoma model and the drug-related toxicities. Cisplatin, carboplatin and mitoxantrone were used as control drugs. In vitro experiments showed a concentration- and time-dependent antiproliferative activity of bile-conjugated platinum complexes. (NH3)2Pt(triacid) had similar effects on cell growth of cisplatin and carboplatin (e.g. at 48 h, IC50 0.7+/-0.05 microM vs. 0.63+/-0.28 microM and 1.1+/-0.3 microM, respectively; mean+/-S.D.). (NH3)2Pt(triacid) was able to inhibit tumour growth in a dose-dependent extent, reaching the maximum inhibitory effect at the 80 mg/kg dose (1.95+/-0.5 g vs. 13.85+/-3.9 g of control tumour weight). By contrast, despite the promising in vitro antiproliferative activity, (PPh3)2Pt(dehydrocholate)2 showed no significant in vivo antitumour effect. The toxicity profile of (NH3)2Pt(triacid) resulted favourable with minimal loss of weight and no gastrointestinal or neurological symptoms. Instead, (PPh3)2Pt(dehydrocholate)2 showed dose-dependent signs of severe weight loss and neurological alterations. In conclusion (NH3)2Pt(triacid) is a tolerable and active platinum derivative endowed by a preclinical antitumour activity by oral route.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Conducta Animal/efectos de los fármacos , Ácidos y Sales Biliares/química , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Neoplasias Hepáticas Experimentales/mortalidad , Neoplasias Hepáticas Experimentales/patología , Masculino , Estructura Molecular , Actividad Motora/efectos de los fármacos , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/química , Platino (Metal)/química , Ratas , Ratas Sprague-Dawley , Tasa de Supervivencia , Factores de TiempoRESUMEN
AIM: To investigate possible associations between VEGFR-2 and IL-8 gene SNPs and 1-year response to intravitreal ranibizumab for exudative age-related macular degeneration. MATERIALS & METHODS: Sixty-four eyes underwent a loading phase of three monthly intravitreal injections of ranibizumab 0.5 mg/0.05 ml followed by Pro Re Nata retreatment. VEGFR-2 rs2071559 (-604 A/G) and IL-8 rs4073 (-251 A/T) were analyzed. RESULTS: Ranibizumab was significantly more effective as measured by visual acuity in patients harboring the IL-8 rs4073 TT genotype (p = 0.045), whereas patients carrying the VEGFR-2 rs2071559 CC genotype revealed better functional response as measured by mean retinal sensitivity (p = 0.034). CONCLUSION: IL-8 rs4073 and VEGFR-2 rs2071559 genotypes may represent important molecular determinants to modulate final outcomes in neovascular age-related macular degeneration patients.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Interleucina-8/genética , Degeneración Macular/tratamiento farmacológico , Ranibizumab/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Fóvea Central/efectos de los fármacos , Fóvea Central/patología , Genotipo , Humanos , Inyecciones Intravítreas , Degeneración Macular/patología , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios ProspectivosRESUMEN
Three novel series of 1,2-benzisothiazole derivatives have been developed as inhibitors of carbonic anhydrase isoform IX. Compounds 5c and 5j, tested in vitro on the human colon cell line HT-29, blocked the growth of cells cultured under chemically induced hypoxic conditions, displaying a specific activity against cancer cells characterized by CAIX up-regulation. Moreover, a synergistic activity of 5c with SN-38 (the active metabolite of irinotecan) and 5-fluorouracil on cell proliferation under hypoxic conditions was demonstrated.
Asunto(s)
Antineoplásicos/farmacología , Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Tiazoles/farmacología , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Anhidrasa Carbónica IX/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
VEGFR-2 and P2X7 receptor (P2X7R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X7R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94-152.96) and 65.65 months (95% CI, 52.95-76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X7R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Receptores Purinérgicos P2X7/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/terapia , Anciano , Anciano de 80 o más Años , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Italia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piranos/farmacología , Pirimidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piranos/síntesis química , Piranos/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The pharmacological control of angiogenesis might represent a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. In order to test this hypothesis, SU5416 ([3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one]) a selective inhibitor of the vascular endothelial growth factor receptor-2 tyrosine kinase, and gemcitabine (2', 2'-difluorodeoxycytidine) were tested on endothelial (HUVEC) and pancreatic tumor cells (MIA PaCa-2) in vitro and in vivo alone and in simultaneous association. SU5416 inhibited HUVEC cells stimulated to proliferate by vascular endothelial growth factor but not MIA PaCa-2 cells; the drug concentration that decreased cell growth by 50% (IC50) was 0.14 microM. Furthermore, SU5416 reduced the development of microvessels from placental explants (IC50, 0.23 microM). Gemcitabine inhibited the growth of both HUVEC and MIA PaCa-2 cells with an IC50 of 0.08 and 0.1 microM, respectively. A synergistic effect (combination index <1 and dose reduction index >1) on anti-proliferative and pro-apoptotic activity was calculated with the simultaneous combination of the two drugs on endothelial cells. A marked in vivo antitumor effect on MIA PaCa-2 xenografts was observed with SU5416 at a protracted schedules, as well as with gemcitabine; furthermore, the combination between the two drugs resulted in an almost complete suppression of tumor growth and relapse. In conclusion, the present results provide the evidence of an effective anti-endothelial/antitumor activity of protracted administration of SU5416 on human pancreas cancer xenografts, which is comparable with the one obtained by gemcitabine; moreover, the synergistic combination between these drugs on endothelial cells and the promising association in pancreatic cancer xenografts could be used in future studies and translated into the clinical setting.
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Apoptosis/efectos de los fármacos , Desoxicitidina/análogos & derivados , Neovascularización Patológica/prevención & control , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/uso terapéutico , División Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Inmunohistoquímica , Indoles/farmacología , Indoles/uso terapéutico , Masculino , Ratones , Ratones Desnudos , Neoplasias Pancreáticas/patología , Placenta/irrigación sanguínea , Placenta/efectos de los fármacos , Embarazo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirroles/farmacología , Pirroles/uso terapéutico , Factores de Tiempo , Técnicas de Cultivo de Tejidos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
AIM: To propose an innovative methodology for the monitoring of the evolution of induced subcutaneous tumors in mice. MATERIALS AND METHODS: A new 3D scanner able to measure the tumor mass volume is presented. The scanner is based on the projection of a fringe pattern onto the sample surface (structured light). The lines are diffused by the sample and then collected by a digital camera. The obtained 2D-image is treated by the scanner's software that extracts the 3D information and evaluates the sample volume. RESULTS: The 3D scanner has been successfully used in the measurement of subcutaneous HT-29 colorectal cancer xenografts treated with 5-fluorouracil, bevacizumab and their combination. Comparison with simple caliper measurements revealed important and significant differences between the two measurement techniques. CONCLUSION: The proposed methodology is more effective than the usual approach based on caliper measurements.
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Neoplasias Colorrectales/diagnóstico , Imagenología Tridimensional , Programas Informáticos , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Fluorouracilo/administración & dosificación , Células HT29 , Humanos , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study was conducted to describe the modulation of plasma epidermal growth factor receptor (EGFR) ligands in EGFR-positive metastatic colorectal cancer (mCRC) patients during treatment with cetuximab and irinotecan and to explore the clinical implication of plasma levels' variations as potential biomarkers of benefit. Plasma amphiregulin (AR), epidermal growth factor (EGF), transforming growth factor-α, and heparin binding-EGF were assessed by ELISA in 45 chemorefractory mCRC patients, treated with cetuximab and irinotecan. Plasma levels were measured before and 1 h after the first administration of cetuximab, before and 1 h after the second administration, and before the third and the fifth cycles. KRAS and BRAF mutational status were determined. EGFR ligands' levels were differently modulated according to tumor KRAS and BRAF mutational status. In KRAS wild-type patients (n = 34), AR and EGF early increased and higher increases were significantly associated with worse clinical outcome. By adopting a specific cut-off value, patients with higher levels of AR 1 h after the first administration had significantly worse response rate, progression free survival, and overall survival. This hypothesis-generating study shows that EGFR ligands are significantly modulated by cetuximab plus irinotecan according to KRAS and BRAF mutational status, and they warrant further investigation as pharmacodynamic markers of resistance to anti-EGFRs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Irinotecán , Ligandos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/genéticaRESUMEN
CONTEXT AND OBJECTIVE: We have studied the antitumor activity of a pyrazolo[3,4-d]pyrimidine compound (CLM3) proposed for a multiple signal transduction inhibition [including the RET tyrosine kinase, epidermal growth factor receptor, and vascular endothelial growth factor (VEGF) receptor and with antiangiogenic activity] in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer), and in an ATC-cell line (AF). DESIGN AND MAIN OUTCOME MEASURES: CLM3 was tested in primary ATC cells at the concentrations of 5, 10, 30, and 50 µM; in 8305C cells, in AF cells, at 1, 5, 10, 30, 50, or 100 µM; and in AF cells in CD nu/nu mice. RESULTS: CLM3 significantly inhibited the proliferation of 8305C and AF cells, also inducing apoptosis. A significant reduction of proliferation with CLM3 in ATC cells (P < .01, ANOVA) was shown. CLM3 increased the percentage of apoptotic ATC cells dose dependently (P < .001, ANOVA) and inhibited migration (P < .01) and invasion (P < .001). The AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 15 days later. CLM3 (50 mg/kg per die) significantly inhibited tumor growth (starting 16 d after the beginning of treatment). CLM3 significantly decreased the VEGF-A expression and microvessel density in AF tumor tissues. Furthermore, CLM3 inhibited epidermal growth factor receptor, AKT, and ERK1/2 phosphorylation and down-regulated cyclin D1 in 8305C and AF cells. CONCLUSIONS: The antitumor and antiangiogenic activity of a pyrazolo[3,4-d]pyrimidine compound (CLM3) is very promising in anaplastic thyroid cancer, opening the way to a future clinical evaluation.
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Inhibidores de la Angiogénesis/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Humanos , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides/irrigación sanguínea , Neoplasias de la Tiroides/patología , Resultado del Tratamiento , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RET(V804L), which still lacks effective inhibitors.
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Inhibidores de Proteínas Quinasas/farmacología , Diseño de Fármacos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/químicaRESUMEN
CLM29 (a pyrazolo[3,4-d]pyrimidine, that inhibits RET, epidermal growth factor receptor, vascular endothelial growth factor receptor, and has an anti-angiogenic activity) has anti-neoplastic activity in papillary dedifferentiated thyroid cancer. Here we tested CLM29 in medullary thyroid cancer (MTC), in primary MTC cells (P-MTC) obtained at surgery, and in TT cells harboring (C634W) RET mutation. CLM29 (10, 30, 50 µM) inhibited significantly (P<0.001) the proliferation, and increased the percentage of apoptotic P-MTC, TT and human dermal microvascular endothelial cells. The inhibition of proliferation by CLM29 was similar in P-MTC cells with/without RET mutation. TT cells were injected sc in CD nu/nu mice, and tumor masses became detectable between 20 and 30 days after xenotransplantation; CLM29 (50mg/kg/die) reduced significantly tumor growth and weight, and microvessel density. The anti-tumor activity of CLM29 has been shown in MTC in vitro, and in vivo, opening the way to a future clinical evaluation.