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2.
Clin Pharmacol Ther ; 100(4): 333-5, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27393720

RESUMO

Although definitions of rare disease vary, most acknowledge that there are small numbers of affected patients compared with other conditions. Small numbers of patients, overlapping involvement of investigators as researchers and caregivers, as well as close relationships between researchers and manufacturers require a different pattern of drug development. Regulatory guidances for rare diseases are available, as well as ones for specific rare diseases. Maintaining drug supply for rare diseases also demands innovative approaches.


Assuntos
Descoberta de Drogas/métodos , Produção de Droga sem Interesse Comercial/normas , Doenças Raras/tratamento farmacológico , Aprovação de Drogas , Guias como Assunto , Humanos
3.
Br J Cancer ; 112(1): 24-31, 2015 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-25268371

RESUMO

BACKGROUND: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). METHODS: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. RESULTS: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg(-1) every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. CONCLUSIONS: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Resultado do Tratamento
4.
Clin Pharmacol Ther ; 96(1): 27-35, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24637941

RESUMO

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/fisiopatologia , Niacinamida/administração & dosagem , Niacinamida/farmacocinética , Compostos de Fenilureia/farmacocinética , Estudos Prospectivos , Sorafenibe , Adulto Jovem
5.
Clin Pharmacol Ther ; 95(4): 370-2, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24440966

RESUMO

Antiretroviral therapy (ART) has significantly reduced morbidity and increased life expectancy of individuals infected with human immunodeficiency virus (HIV). Consequently, non-acquired immunodeficiency syndrome (AIDS)-defining malignancies are increasing in frequency, which necessitates the concurrent use of antineoplastics and ART. Although drug interactions are a major concern when combining these agents, there is currently limited guidance on dose adjustments required to maintain safe and efficacious drug exposure.


Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Neoplasias/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Fármacos Anti-HIV/administração & dosagem , Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Infecções por HIV/epidemiologia , Infecções por HIV/fisiopatologia , Humanos , Expectativa de Vida , Neoplasias/epidemiologia
6.
Prostate Cancer Prostatic Dis ; 16(4): 357-61, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23958896

RESUMO

BACKGROUND: Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer (PCa) cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible. METHODS: We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent PCa after local therapy. Dose escalation occurred if a demethylating 'response' (that is, 10% decrease in peripheral blood mononuclear cell (PBMC) global 5-methyl cytosine (5(me)C) content) was observed in <3 patients in cohort 1. Cohorts 1 and 2 received disulfiram 250 mg and 500 mg daily, respectively. The primary end point was the proportion of subjects with a demethylation response. Secondary end points included the rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability. RESULTS: Changes in global 5(me)C content were observed in two of nine patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only five subjects were on trial for 6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with six patients experiencing grade 3 adverse events (three per cohort). Three of the responders displayed pretreatment instability in their 5(me)C content. CONCLUSIONS: A minority of patients had transient global PBMC demethylation changes. Instability in 5(me)C may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population.


Assuntos
Antineoplásicos/farmacocinética , Dissulfiram/farmacocinética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Idoso , Antineoplásicos/efeitos adversos , Ceruloplasmina/metabolismo , Metilação de DNA/efeitos dos fármacos , Dissulfiram/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/genética
7.
Br J Cancer ; 106(1): 77-84, 2012 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-22134508

RESUMO

BACKGROUND: Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours. METHODS: Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m(-2) with a fixed dose of CRA at 1 mg kg(-1) per day. Entinostat dose was escalated by 1 mg m(-2) increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition. RESULTS: A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m(-2) dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression. CONCLUSION: The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m(-2) once weekly and CRA 1 mg kg(-1) per day. Although no tumour responses were seen, further evaluation of this combination is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzamidas/administração & dosagem , Western Blotting , Cromatografia Líquida , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Isotretinoína/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Piridinas/administração & dosagem , Espectrometria de Massas em Tandem , Resultado do Tratamento
8.
Br J Cancer ; 103(5): 649-55, 2010 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-20664591

RESUMO

BACKGROUND: The purpose of this work was to determine the efficacy of inhibiting mammalian target of rapamycin (mTOR) in pancreatic cancer preclinical models and translate preclinical observations to the clinic. METHODS: Temsirolimus (20 mg Kg(-1) daily) was administered to freshly generated pancreatic cancer xenografts. Tumour growth inhibition was determined after 28 days. Xenografts were characterised at baseline by gene expression and comparative genomic hybridisation. Patients with advanced, gemcitabine-resistant pancreatic cancer were treated with sirolimus (5 mg daily). The primary end point was 6-month survival rate (6mSR). Correlative studies included immunohistochemistry assessment of pathway expression in baseline tumours, drug pharmacokinetics (PKs), response assessment by FDG-PET and pharmacodynamic effects in peripheral-blood mononuclear cells (PBMCs). RESULTS: In all, 4 of 17 xenografts (23%) responded to treatment. Sensitive tumours were characterised by gene copy number variations and overexpression of genes leading to activation of the PI3K/Akt/mTOR pathway. Activation of p70S6K correlated with drug activity in the preclinical studies. Sirolimus was well tolerated in the clinic, showed predictable PKs, exerted pathway inhibition in post-treatment PBMCs and resulted in a 6mSR of 26%. No correlation, however, was found between activated p70S6K in tumour tissues and anti-tumour effects. CONCLUSION: Sirolimus activity in pancreatic cancer was marginal and not predicted by the selected biomarker.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antibióticos Antineoplásicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Sirolimo/uso terapêutico , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Leukemia ; 24(8): 1437-44, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20535150

RESUMO

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities >or=grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. x 21 days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Recidiva , Sorafenibe , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
10.
Oncogene ; 28(4): 610-8, 2009 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-19029951

RESUMO

The pupose of this study was to evaluate the activity of ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of pancreatic cancer and to discover biomarkers predictive of efficacy. Successive in vitro and in vivo models were used; these included cell line-derived and patient-derived tumors from our PancXenoBank, a live collection of freshly generated pancreatic cancer xenografts. ON 01910.Na showed equivalent activity to gemcitabine against pancreatic cancer cell lines in vitro. The activity of the agent correlated with suppression of phospho-CDC25C and cyclin B1. These markers were optimized for a fine-needle aspirate ex vivo rapid assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Next, nine patient-derived tumors from the PancXenoBank were profiled using the assay developed in cell lines and treated with ON01910.Na for 28 days. Two cases were cataloged as potential responders and seven as resistants. There was a correlation between the ex vivo assay and sensitivity to the tested agent, as the two cases prospectively identified as sensitive met prespecified criteria for response. Of the seven tumors of predictive resistant, only one was found to be sensitive to ON 01910.Na. In addition, there was a good correlation between cyclin B1 downregulation ex vivo and changes in cyclin B1 protein post-treatment. The novel mitotic inhibitor, ON 01910.Na, showed activity in preclinical model of pancreatic cancer. A rapid assay was rationally developed that not only identified cases sensitive to ON 01910.Na, but also anticipated the pharmacodynamic events occurring after in vivo exposure.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glicina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Biópsia por Agulha Fina , Linhagem Celular Tumoral , Ciclina B/metabolismo , Ciclina B1 , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Sulfonas/uso terapêutico , Fosfatases cdc25/metabolismo , Gencitabina
11.
Eur J Cancer ; 40(8): 1170-8, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15110880

RESUMO

Current dosing strategies for anticancer drugs result in wide interindividual pharmacokinetic variability. Here, we explored the influence of age, body size, concomitant drugs, dose, infusion duration, and sex on the clearance for doxorubicin and docetaxel in 243 individual patients. Patients received doxorubicin (n=110) or docetaxel (n=152) as monotherapy or in combination chemotherapy regimens. The mean (+/-S.D.) clearance was 63.6+/-22.7 L/h for doxorubicin and 42.8+/-14.9 L/h for docetaxel. Normalisation for body surface area (BSA) reduced the interindividual variability by only <1.7%. Doxorubicin clearance was significantly reduced when administered at doses >50 mg/m(2) or in combination with cyclophosphamide. Upper extremes of body size were associated with increased clearance for both drugs, whereas no consistent effect of age on clearance was discerned. Overall, these findings suggest that incorporation of variables in addition to BSA should be considered in routine dosing strategies for doxorubicin and docetaxel.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Fitogênicos/farmacocinética , Doxorrubicina/farmacocinética , Taxoides/farmacocinética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Constituição Corporal , Índice de Massa Corporal , Docetaxel , Doxorrubicina/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Taxoides/administração & dosagem
12.
Arch Dermatol ; 137(4): 471-4, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11295928

RESUMO

BACKGROUND: Anti-angiogenesis is an exciting new approach to anticancer therapy. COL-3, a tetracycline derivative, is a novel anti-angiogenesis agent with potent preclinical anticancer activity. During the conduct of a phase 1 clinical trial for refractory metastatic cancer at the National Institutes of Health, we observed 3 individuals who developed phototoxicity followed by clinical and laboratory features of drug-induced lupus. OBSERVATIONS: Three of 35 patients treated with COL-3 developed sunburnlike eruptions accompanied by fever and a positive antinuclear antibody titer within 8 to 29 days of starting treatment. Two of 3 had positive antihistone antibody levels and arthralgia. One patient had marked systemic manifestations including pulmonary infiltrates and elevated erythrocyte sedimentation rate remittent for more than 1 year after discontinuing COL-3 treatment. The other 2 patients' symptoms and rash abated within 2 weeks of discontinuing therapy although the serologic markers remained abnormal for the duration of follow-up. CONCLUSIONS: COL-3 is the second tetracycline derivative to be implicated in the development of drug-induced lupus. A sunburnlike eruption immediately preceded or accompanied the systemic and serologic changes in these 3 patients. The rapid onset and the phototoxic appearance of the accompanying eruptions might suggest that damage to the keratinocytes caused the formation of neoantigens to which autoantibodies formed.


Assuntos
Lúpus Eritematoso Cutâneo/induzido quimicamente , Inibidores de Metaloproteinases de Matriz , Metástase Neoplásica/tratamento farmacológico , Inibidores de Proteases/efeitos adversos , Tetraciclinas/efeitos adversos , Administração Tópica , Idoso , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Clobetasol/administração & dosagem , Clobetasol/análogos & derivados , Feminino , Seguimentos , Glucocorticoides , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pomadas , Prednisona/uso terapêutico , Fatores de Tempo
13.
Am J Hematol ; 67(1): 51-3, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11279658

RESUMO

Eight of 35 patients with cancer receiving COL-3, a tetracycline derivative with antiangiogenic properties, developed anemia while on treatment. All of these patients were enrolled on an approved Phase I clinical trial at the National Cancer Institute. Three of these patients had bone marrow examinations that revealed ringed sideroblasts. This paper describes these cases. Am. J. Hematol. 67:51-53, 2001. Published 2001 Wiley-Liss, Inc.


Assuntos
Anemia Sideroblástica/induzido quimicamente , Tetraciclina/efeitos adversos , Adenocarcinoma Folicular/complicações , Adenocarcinoma Folicular/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tetraciclina/administração & dosagem , Tetraciclinas , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/tratamento farmacológico
14.
J Clin Oncol ; 19(2): 584-92, 2001 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-11208854

RESUMO

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Inibidores de Metaloproteinases de Matriz , Neoplasias/tratamento farmacológico , Tetraciclinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacocinética , Fatores de Crescimento Endotelial/sangue , Inibidores Enzimáticos/farmacocinética , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Linfocinas/sangue , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Tetraciclinas/farmacocinética , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular
15.
Biomed Chromatogr ; 14(5): 338-43, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10960835

RESUMO

UCN-01, 7-hydroxystaurosporine, is an antagonist of protein kinase C, as well as causing cell cycle arrest. We developed and validated an HPLC assay method for the quantitation of UCN-01. Plasma and saliva standard curves were prepared at concentrations ranging from 0.2 to 20.0 microgram/mL and 4.0 to 200.0 ng/mL, respectively. The sample preparation consisted of acetonitrile precipitation. Separation was accomplished on a phenyl column and a C-18 precolumn insert utilizing a gradient-profile consisting of ammonium acetate and acetonitrile. UV detection was set at 295 nm for UCN-01 and 323 nm for umbelliferone, the internal standard. For fluorescence detection, excitation occurred at 290 nm, while emission was at 400 nm. The retention times were around 4 min for umbelliferone and 9.1 for UCN-01. Inter- and intra-assay errors of accuracy were less than 7. 0% and 10.7%, respectively, for the plasma standard curve and less than 7.1% and 6.7%, respectively, for the saliva standard curve. The recoveries of UCN-01 and umbelliferone from saliva were 81.4 +/- 0. 9% and 106.3 +/- 10.2%, respectively. The recovery of UCN-01 from plasma was 97.9 +/- 7.1% and for umbelliferone was 103.3 +/- 2.3%. This method is suitable for quantifying UCN-01 in patient samples and further characterizing the clinical pharmacology of this compound. Published in 2000 by John Wiley & Sons, Ltd.


Assuntos
Alcaloides/análise , Cromatografia Líquida de Alta Pressão/métodos , Inibidores Enzimáticos/análise , Saliva/química , Alcaloides/sangue , Calibragem , Inibidores Enzimáticos/sangue , Humanos , Proteína Quinase C/antagonistas & inibidores , Reprodutibilidade dos Testes , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Estaurosporina/análogos & derivados
16.
J Pharm Biomed Anal ; 22(6): 1003-14, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10857569

RESUMO

COL-3, 6-deoxy-6-demethyl-4-dedimethylamino-tetracycline, is a matrix metalloproteinase inhibitor. A specific and sensitive analytical method was necessary to quantitate the analyte in human plasma. High-performance liquid chromatography with atmospheric pressure chemical ionization mass spectrometry detection was utilized to quantitate COL-3 from 30 to 10,000 ng/ml in two calibration curves: 30-1,500 and 400-10,000 ng/ml. The sample preparation consisted of acetonitrile precipitation for all plasma samples. COL-3 is separated on a Waters Symmetry C-18 (2.1 x 150 mm) column with oxalic acid (0.01 M, pH 2.2)-acetonitrile mobile phase. The total run time was 23 min. Identification of COL-3 and the internal standard was through positive chemical ionization and selective ion monitoring. A quantifying and qualifying ion for COL-3 is used to verify the presence of COL-3 in patient samples. Inter- and intra-run mean percent errors for all of the quality controls were less than 18.3', and relative standard deviations were all less than 14.9'% Recovery of COL-3 and the internal standard was approximately 55 and 72', respectively. Freeze thaw stability of COL-3 was variable. This method is suitable for quantifying COL-3 in patient samples and to further characterize the clinical pharmacology of this compound.


Assuntos
Antibióticos Antineoplásicos/sangue , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/sangue , Tetraciclina/sangue , Calibragem , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Congelamento , Humanos , Espectrometria de Massas , Controle de Qualidade , Tetraciclinas
17.
Biochem Biophys Res Commun ; 268(1): 183-91, 2000 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-10652234

RESUMO

Endostatin has demonstrated potent antiangiogenic and antitumor activity in mouse models. We have investigated the ex vivo rat aortic ring assay and a human vein model to assess the biological activity of murine and human endostatin. Rat aortic rings were exposed to recombinant murine endostatin (Spodoptera frugipera; Calbiochem, San Diego, CA) or recombinant human endostatin (Pichia pastoris; EntreMed, Rockville, MD). After 5 days, murine endostatin (500 microgram/ml) demonstrated inhibition of microvessel outgrowth with dose-dependent effects (down to 16 microgram/ml). No significant inhibition was observed with human endostatin in the rat assay. Human endostatin at 250 and 500 microgram/ml inhibited outgrowths from human saphenous vein rings after a 14-day incubation. Electron microscopy assessed the formation of basal lamina, confirming that the microvessels were progenitors of patent vessels. Immunostaining for Factor VIII or CD34 demonstrated that the microvessel cells were endothelial. BrdU incorporation assays supported the presence of proliferating endothelial cells, correlating with neovascularization from the aortic wall. We conclude that the rat aortic ring assay confirms the antiangiogenic activity of murine but not human endostatin, suggesting that the model may have species specificity. However, the human form shows biological activity against human vascular tissue.


Assuntos
Inibidores da Angiogênese/farmacologia , Aorta Torácica/efeitos dos fármacos , Colágeno/farmacologia , Fragmentos de Peptídeos/farmacologia , Inibidores da Angiogênese/genética , Animais , Antígenos CD34/metabolismo , Colágeno/genética , Endostatinas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Microscopia Eletrônica , Neovascularização Fisiológica/efeitos dos fármacos , Fragmentos de Peptídeos/genética , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacologia , Veia Safena/efeitos dos fármacos , Especificidade da Espécie
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