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The detection and characterisation of tumour-derived circulating epithelial tumor cells (CETCs) or circulating tumor cells (CTCs) have been a main focus of basic oncological research over previous years. Numerous studies in the past decade have shown that CTCs are a promising tool for the estimation of the risk for metastatic relapse. The present observational study describes treatment results using tumour imaging and the quantification of CTCs. A group of 14 patients with advanced carcinomas was followed during their anticancer treatments. CTC numbers were serially detected and treatment success was estimated by positron emission tomography-computed tomography. A connection was found between tumour remission and a decreasing CTC count in 83%, a connection between stable disease and stable CTC numbers in 78% and a connection between progressive disease (PD) and an increase in CTC count in 50% of cases. In the patients with PD, an incomplete response was observed affecting the CTCs, but not the solid region of the tumour. As a result of this study, it may be concluded that patients with solid tumours benefit from serial quantification of CTCs in addition to imaging, as this combination of techniques provides a more sensitive result than imaging alone.
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PURPOSE: Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer models. This first-in-human study aimed to assess the safety, tolerability, and pharmacokinetics of Atu027 while evaluating therapeutic effects on both primary tumors and metastatic lesions. PATIENTS AND METHODS: Thirty-four patients with advanced solid tumors received 10 escalating doses of Atu027 without premedication, as one single followed by eight intravenous infusions twice per week during a 28-day cycle. Response was monitored by computed tomography/magnetic resonance imaging at baseline, at the end of treatment (EoT), and at final follow-up (EoS), and was assessed according to RECIST. RESULTS: Atu027 was well tolerated up to dose levels of 0.336 mg/kg; most adverse events (AEs) were low-grade toxicities (grade 1 or 2). No maximum tolerated dose was reached. Plasma levels of siRNA strands and lipids were dose proportional, peaking during 4-hour infusion. Disease stabilization was achieved in 41% of patients at EoT (n = 14 of 34 treated patients); eight patients had stable disease at EoS, and some experienced complete or partial regression of metastases. sFLT1 (soluble variant of vascular endothelial growth factor receptor-1) decreased from pretreatment levels in most patients after dose levels 04 to 10. CONCLUSION: Atu027 was safe in patients with advanced solid tumors, with 41% of patients having stable disease for at least 8 weeks. In view of these results, further clinical trials have been initiated, and sFLT1 will be investigated as a potential biomarker.
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Neoplasias/tratamiento farmacológico , Proteína Quinasa C/antagonistas & inhibidores , ARN Interferente Pequeño/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Proteínas del Sistema Complemento/análisis , Citocinas/sangre , Femenino , Humanos , Liposomas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteína Quinasa C/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacocinéticaRESUMEN
UNLABELLED: Combining different targeted anticancer agents may improve clinical outcomes. This Phase I study investigated cediranib, an oral inhibitor of vascular endothelial growth factor signalling in combination with saracatinib, an oral Src inhibitor. The primary endpoint was safety/tolerability. Secondary assessments included pharmacokinetics and preliminary efficacy. PATIENTS AND METHODS: Patients with advanced solid tumours received cediranib 20, 30 or 45 mg/day for 7 days followed by daily treatment with cediranib at the same dose plus saracatinib 175 mg/day. RESULTS: Thirty-nine patients received cediranib (20 mg, n = 6; 30 mg, n = 6; 45 mg, n = 27 [n = 20 in cohort expansion]) plus saracatinib. In the cediranib 45 mg cohort, 59% of patients required dose reduction/pause compared with 33% in each of the other two cohorts. There was one dose-limiting toxicity (hypertension; 45 mg cohort). The most common adverse events were hypertension (67%), diarrhoea (62%), dysphonia (46%) and fatigue (39%). There was no evidence of a clinically significant effect of saracatinib on cediranib pharmacokinetics and vice versa. 22/35 evaluable patients had a best response of stable disease. CONCLUSIONS: All cediranib doses were tolerated; however, in patients with advanced solid tumours, for combination with saracatinib 175 mg/day, cediranib 20 or 30 mg/day was more sustainable than 45 mg/day.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzodioxoles/administración & dosificación , Benzodioxoles/efectos adversos , Benzodioxoles/farmacocinética , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Familia-src Quinasas/metabolismoAsunto(s)
Neoplasias/terapia , Proteína Quinasa C/genética , ARN Interferente Pequeño/farmacología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Neoplasias/genética , Neoplasias/patología , ARN Interferente Pequeño/administración & dosificación , Resultado del TratamientoRESUMEN
Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies.
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Inhibidores de la Angiogénesis/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias/terapia , Anticuerpos Monoclonales/uso terapéutico , Biomarcadores de Tumor/sangre , Humanos , Imagen por Resonancia Magnética , Neoplasias/diagnóstico , Neoplasias/metabolismo , Células Neoplásicas Circulantes , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Hepatocellular carcinoma (HCC) has a poor prognosis and systemic chemotherapies have disappointing results. The increasing knowledge of the molecular biology of HCC has resulted in novel targets, with the vascular endothelial growth factor and epidermal growth factor receptor (EGFR)-related pathways being of special interest. New blood vessel formation (angiogenesis) is essential for the growth of solid tumors. Anti-angiogenic strategies have become an important therapeutic modality for solid tumors. Several agents targeting angiogenesis-related pathways have entered clinical trials or have been already approved for the treatment of solid tumors. These include monoclonal antibodies, receptor tyrosine kinase inhibitors and immunomodulatory drugs. HCC is a highly vascular tumor, and angiogenesis is believed to play an important role in its development and progression. This review summarizes recent advances in the basic understanding of the role of angiogenesis in HCC as well as clinical trials with novel therapeutic approaches targeting angiogenesis and EGFR-related pathways.
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BACKGROUND: PTK787/ZK 222584 (PTK/ZK) offers a novel approach to inhibit tumour angiogenesis. PATIENTS AND METHODS: This study characterized the safety, tolerability, biological activity and pharmacokinetic profile of PTK/ZK, while determining the optimum dose. Seventy-one patients with advanced cancer were enrolled to receive once daily dosing. Pharmacokinetic, dynamic contrast enhanced magnetic resonance imaging and safety assessments were performed, along with measurement of soluble markers. Patients were treated until they had unacceptable toxicity and/or disease progression. RESULTS: Twenty-nine patients were assessable for maximum tolerated dose (MTD) determination, but no MTD was established; only two patients experienced dose limiting toxicities. PTK/ZK was well tolerated with only nine patients experiencing serious adverse events suspected to be PTK/ZK related, but no objective tumour response was observed; 34% had stable disease and 48% had progressive disease. In addition, PTK/ZK was rapidly absorbed with a maximum concentration occurring 2 hours post-dosing. Vascular endothelial growth factor and basic fibroblastic growth factor were good predictors of best tumour response, as was the MRI bidirectional transfer constant on day 2 of treatment. CONCLUSION: An MTD was not reached in this study but, based on these data and findings from other studies, 1200 mg was found to be the optimum dose of PTK/ZK for patients with advanced cancer.
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Neoplasias/tratamiento farmacológico , Ftalazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Administración Oral , Esquema de Medicación , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Humanos , Imagen por Resonancia Magnética , Masculino , Dosis Máxima Tolerada , Neoplasias/sangre , Neoplasias/patología , Ftalazinas/efectos adversos , Piridinas/efectos adversos , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Auron-Misheil-Therapy (AMT) is a defined but unique combination of approved pharmaceuticals. It consists of insulin, chlorpheniramine and an aqueous camomile extract, and it has been successfully applied clinically in late-stage cancer patients. The purpose of this study was to elucidate the anti-tumor efficacy of AMT in a validated murine renal cell carcinoma animal model (RENCA). There were two independent studies; each animal group consisted of 16 mice. During a 6-week pretreatment period, vehicle (group A) and AMT (1.6 mg/kg/d) (group B) were administered once daily in a 5 days/week schedule either intramuscularly or subcutaneously. Tumor challenge at day 0 was followed by a 3-week treatment period (either vehicle or AMT once daily intramuscularly for 21 days consecutively). In study 2 the AMT dosage was increased up to 4-fold by doubling individual doses and switching to a twice daily schedule. The injections were all intramuscular. With the exception of group D, a six-week pretreatment period preceded the tumor challenge at day 0. Tumor challenge was followed by a 3-week treatment period (vehicle, AMT at either 3.2 mg/kg/d) (group A) or 6.4 mg/kg/d (group B), or AMT0, an AMT preparation which does not stimulate IL-6 secretion (6.4 mg/kg/d, group C) continuously for 21 days. AMT administration for group D (6.4 mg/kg/d) was limited to the treatment period from day 1 to 21. All mice were sacrificed 21 days after tumour transplantation. AMT administration was safe and well tolerated, and significantly reduced primary tumor volume in pretreated animals. The effective route of application was intramuscular, with dose escalation resulting in an improved anti-tumor effect. This is the first demonstration of a significant anti-tumorigenic effect of AMT in a validated tumor model.
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Antineoplásicos/uso terapéutico , Calcio/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Clorfeniramina/uso terapéutico , Insulina/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Factores de TiempoRESUMEN
PURPOSE Hypertension is a commonly reported adverse effect after administration of vascular endothelial growth factor (VEGF) inhibitors. Cediranib is a highly potent and selective VEGF signaling inhibitor of all three VEGFRs. This study prospectively investigated hypertension management to help minimize dose interruptions/reductions to maximize cediranib dose intensity. PATIENTS AND METHODS Patients (n = 126) with advanced solid tumors were randomly assigned to one of four groups: cediranib 30 or 45 mg/d with or without antihypertensive prophylaxis. All patients developing hypertension on cediranib treatment were treated with a standardized, predefined hypertension management protocol. Results Cediranib was generally well tolerated, and all groups achieved high-dose intensities in the first 12 weeks (> 74% in all groups). Antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. Increases in blood pressure, including moderate and severe readings of hypertension, were seen early in treatment in all groups and successfully managed. Severe hypertension occurred in one patient receiving prophylaxis versus 18 in the nonprophylaxis groups. Overall, there were nine partial responses, and 38 patients experienced stable disease >/= 8 weeks. CONCLUSION To our knowledge, this is the first prospective investigation of hypertension management during administration of a VEGF signaling inhibitor. All four regimens were well tolerated with high-dose intensities and no strategy was clearly superior. The current cediranib hypertension management protocol appears to be effective in managing hypertension compared with previous cediranib studies where no plan was in place, and early recognition and treatment of hypertension is likely to reduce the number of severe hypertension events. This protocol is included in all ongoing cediranib clinical studies.
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Antihipertensivos/uso terapéutico , Hipertensión/inducido químicamente , Hipertensión/prevención & control , Neoplasias/tratamiento farmacológico , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Estudios Prospectivos , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto JovenRESUMEN
This pilot study of Auron Misheil Therapy (AMT) in women with advanced cervical cancer was an open-label, single arm study to collect initial safety, efficacy, and quality of life data. Fifteen women with stage IIIb or IVa cervical cancer were given twice daily intramuscular injections of AMT (insulin, chlorpheniramine and camomile extract) for 3 months. Objective tumor response was evaluated using CT scans and analyzing the data according to the WHO RECIST criteria. Clinical Benefit Response (CBR) was assessed using a composite score comprising Karnovsky performance status, pain intensity and body weight. Safety and tolerability parameters were monitored. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC C-30). Eight out of 15 patients were rated as clinical responders (CBR) at 12 weeks. One patient had a partial response and 11 stable disease (WHO RECIST criteria). AMT was well tolerated. An initial analysis showed improvement in quality of life (EORTC C-30). Promising response rates, early indications of improved quality of life, and no significant safety issues mean that the second, randomized phase of the trial can be initiated with a longer treatment duration. Patients with advanced cervical cancer showed positive clinical responses to Auron Misheil Therapy. The treatment was well tolerated, with indications of improved quality of life.
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Antineoplásicos/uso terapéutico , Calcio/uso terapéutico , Clorfeniramina/uso terapéutico , Insulina/uso terapéutico , Extractos Vegetales/uso terapéutico , Calidad de Vida , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patologíaRESUMEN
The established role of VEGF signaling in promoting tumor angiogenesis has led to the development and clinical validation of several agents that selectively target this pathway in patients with advanced-stage malignancies. These include neutralizing anti-VEGF monoclonal antibodies, soluble VEGF receptors and small-molecule inhibitors of VEGF receptor function, administered either as monotherapy or in combination with chemotherapy. Several modes of action have been identified, such as inhibition of new vessel growth, regression of newly formed vasculature, alteration of tumor vessel function and direct effects on tumor cells. VEGF-targeting drugs currently play an important role in the treatment of cancer and their impact will probably further increase in the future.
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Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados , Bevacizumab , Humanos , Neoplasias/metabolismoRESUMEN
Auron-Misheil-Therapy (AMT) consisting of aqueous camomile extract supplemented with calcium, vitamins, the antihistamine chlorpheniramine and human insulin is under development as anti-cancer treatment. AMT was preclinically investigated in tumour cell lines and tumour xenografts to guide clinical phase I/II studies. AMT was tested against 56 human tumour cell lines, in a clonogenic assay in 98 patient-derived xenografts and in in vivo studies. AMT showed in vitro cytotoxic activity with highest susceptibility in cervical cancer, glioblastoma and colon cancers. In the clonogenic assay, anti- cancer activity of AMT was most active in cervical and uterine tumours, in colon cancer, glioblastoma, leukaemia, melanoma and pancreatic cancer. In vivo, AMT showed slight activity in tumour xenograft models of colon and mammary cancer. It also showed immune stimulatory effects by induction of IL-6- and TNF-alpha secretion in human PBMCs. The immune stimulatory potential of AMT, together with slight anti-tumour efficacy observed in the present study, indicates a role of AMT in tumour therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Manzanilla/química , Neoplasias/patología , Extractos Vegetales/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Calcio/farmacología , Calcio/uso terapéutico , Células Cultivadas , Clorfeniramina/farmacología , Clorfeniramina/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Insulina/farmacología , Insulina/uso terapéutico , Ratones , Neoplasias/tratamiento farmacológico , Especificidad de Órganos/efectos de los fármacos , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Resultado del TratamientoRESUMEN
This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and mammalian target of rapamycin (mTOR) signaling in the treatment of solid tumors. Such targeted agents can be divided into monoclonal antibodies, tyrosine kinase inhibitors, multitargeted tyrosine kinase inhibitors and serine/threonine kinase inhibitors. Molecular targeted therapies are generally well tolerated, but inhibitory effects on the biological function of the targets in healthy tissue can result in specific treatment-related side effects, particularly with multitargeted agents. We offer some guidance on how to manage adverse events in cancer patients based on the range of options currently available.
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Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Humanos , Resultado del TratamientoRESUMEN
Cediranib is a highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor with activity against all three VEGF receptors (VEGFRs) that inhibits angiogenesis and growth of human tumor xenografts in vivo. The present study evaluated the antitumor and antiangiogenic activity of cediranib in the clinically relevant, murine renal cell carcinoma (RENCA) model and its biological response using VEGF and sVEGFR-2 as biomarkers. Mice were treated with cediranib (5 mg/kg/d p.o.) or vehicle for 2, 8 or 12 days and tumor volumes, microvessel density (MVD) and VEGF and sVEGFR-2 plasma concentrations were determined. Cediranib treatment (8 and 12 days) led to a significant reduction in tumor size (42-50%) and a highly significant reduction in MVD (30-55%) versus controls. After 12 days' treatment, VEGF plasma concentration increased significantly in both cediranib-treated and control animals and this increase correlated with tumor size; the cediranib group showed a more pronounced increase in VEGF but a reduced tumor volume compared with control animals. Plasma concentrations of VEGF reached a plateau in the cediranib group after 17-21 days' treatment. sVEGFR-2 concentrations significantly decreased over 12 days in controls, whereas they remained stable in cediranib-treated mice. sVEGFR-2 did not correlate with tumor volume in controls; mice treated with cediranib had lower relative VEGFR-2 plasma concentrations and tumor burdens. In conclusion, cediranib showed potent antitumor and antiangiogenic efficacy in the RENCA model. sVEGFR-2 plasma concentrations can act as a surrogate marker for antitumor activity of VEGFR signaling inhibitors.
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Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Modelos Animales de Enfermedad , Neoplasias Renales/tratamiento farmacológico , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Quinazolinas/farmacología , Animales , Carcinoma de Células Renales/irrigación sanguínea , Carcinoma de Células Renales/patología , Femenino , Técnicas para Inmunoenzimas , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Receptores de Factores de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND AND OBJECTIVE: In a phase-III trial it was recently shown that an adjuvant renal cell carcinoma (RCC) vaccine (Reniale) reduces the risk of tumour progression following nephrectomy. This clinical trial focused on efficacy and did not investigate end-points relating to mode-of-action of the vaccine. In a murine model we investigated mode-of-action, efficacy, and safety of a homologous RENCA cell-based vaccine. DESIGN, SETTING, AND PARTICIPANTS: Six groups with 12 BALB/c mice per group received five vaccinations (lysate of 1x10(6)-1x10(7) RENCA cells, manufactured with or without prior IFN-gamma incubation) at 3-wk intervals before tumour transplantation and one vaccination 14 d afterwards. Controls (12 mice) received only solvent. All mice were sacrificed 21 d after tumour transplantation. MEASUREMENTS: Animal welfare, tumour growth, number of metastases, and the presence of cytotoxic T-lymphocytes as determined by a (51)chromium-release assay. Adoptive immune transfer experiments (vaccination of nine mice with the RENCA vaccine or saline and transfer of serum, spleen cells, and CD4 and/or CD8 depleted spleen cells into five recipient mice each) were carried out to demonstrate involvement of different immune mechanisms. RESULTS: All controls developed a renal tumour, compared to 7/72 animals (9.7%) in the vaccine groups. The mean number of lung metastases was 100 (range 3-750) in controls and 4 (range 0-196) in the vaccine groups, respectively. Tumour uptake and number of metastases were not related to the vaccine dose. The (51)chromium-release assay confirmed a significant tumour-specific cytolytic activity and marginally increased NK activity of splenocytes from vaccinated mice against RENCA cells compared to controls. Adoptive immune transfer experiments showed that the antitumoural effective immune mechanisms are cell-based. CONCLUSIONS: We could demonstrate the mode-of-action, efficacy, and safety of a homologous tumour vaccine in a RENCA model. These findings support the positive results from a phase-III trial with Reniale.
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Vacunas contra el Cáncer/inmunología , Carcinoma de Células Renales/prevención & control , Neoplasias Renales/prevención & control , Inmunidad Adaptativa , Traslado Adoptivo , Animales , Vacunas contra el Cáncer/farmacología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Línea Celular Tumoral , Terapia Combinada , Modelos Animales de Enfermedad , Femenino , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Células Asesinas Naturales/inmunología , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Nefrectomía , Bazo/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Carga Tumoral/inmunologíaRESUMEN
BACKGROUND: Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated. MATERIALS AND METHODS: The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration. RESULTS: Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2xd and 200 Bg/kg 1xd, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model. CONCLUSION: The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.
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Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Ácido Clodrónico/uso terapéutico , Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Animales , Conservadores de la Densidad Ósea/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas/metabolismo , Ácido ZoledrónicoRESUMEN
BACKGROUND: Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects. MATERIAL AND METHODS: 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 x 500 mg oral capecitabine/ day and 2 x 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue. RESULTS: Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression. CONCLUSION: Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Administración Oral , Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Celecoxib , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/irrigación sanguínea , Pirazoles/efectos adversos , Sulfonamidas/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity. EXPERIMENTAL DESIGN: A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents. RESULTS: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission. CONCLUSIONS: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2.
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Antibióticos Antineoplásicos/efectos adversos , Doxorrubicina/análogos & derivados , Hidrazonas/efectos adversos , Neoplasias/tratamiento farmacológico , Profármacos/efectos adversos , Adulto , Anciano , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Femenino , Corazón/efectos de los fármacos , Humanos , Hidrazonas/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Profármacos/farmacocinética , Piel/efectos de los fármacosRESUMEN
PURPOSE: AZD2171 is a highly potent oral selective inhibitor of vascular endothelial growth factor (VEGF) signaling. This phase I study was designed to evaluate the safety and tolerability of increasing doses of AZD2171, with additional assessments of pharmacokinetics, pharmacodynamics, and efficacy. PATIENTS AND METHODS: In part A, 36 patients with solid tumors and liver metastases refractory to standard therapies received once-daily oral AZD2171 (0.5 to 60 mg). Doses were escalated in successive cohorts until the maximum-tolerated dose was identified. In part B, patients with (n = 36) or without (n = 11) liver metastases were randomly assigned to receive once-daily AZD2171 (20, 30, or 45 mg). In both parts, treatment continued until tumor progression or dose-limiting toxicity (DLT) was observed. RESULTS: Eighty-three patients received AZD2171, which was generally well tolerated at doses of 45 mg/d or less; the most frequently reported dose-related adverse events were diarrhea, dysphonia, and hypertension. The most common DLT was hypertension (n = 7), which occurred at AZD2171 doses of 20 mg and higher. After a single dose, maximum plasma (peak) drug concentration after single-dose administration (Cmax) was achieved 1 to 8 hours postdosing with an arithmetic mean half-life associated with terminal slope of a semilogarithmic concentration-time curve (t1/2 lamda(z)) of 22 hours. Pharmacodynamic assessments demonstrated time-, dose-, and exposure-related decreases in initial area under the curve, defined over 60 seconds post-contrast arrival in the tissue (iAUC60) using dynamic contrast-enhanced magnetic resonance imaging, as well as dose- and time-dependent reductions in soluble VEGF receptor 2 levels. Preliminary evidence of efficacy included two confirmed partial responses and 22 patients with stable disease; effects on tumor size appeared to be dose related. CONCLUSION: Once-daily oral AZD2171 at doses of 45 mg or less was generally well tolerated and was associated with encouraging antitumor activity in patients with a broad range of advanced solid tumors.
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Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Quinazolinas/administración & dosificación , Quinazolinas/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias/patología , Quinazolinas/efectos adversos , Medición de Riesgo , Método Simple Ciego , Análisis de Supervivencia , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/uso terapéuticoRESUMEN
PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.