RESUMEN
AIM: To assess the effectiveness of the implementation of a protocol for glycaemic control in critical care, in terms of maintenance of a pre-established target of blood glucose level, reduction of hyperglycaemia and prevention of severe hypoglycaemia. METHOD: Prospective "pre-post" quasi-experimental study carried out in a general critical care unit. Adult patients treated with intravenous insulin were included. We recorded all glycaemic tests performed from November 2014 to August 2015 (pre-intervention) and from November 2015 to August 2016 (post-intervention). The intervention consisted of the implementation of an evidence-based glycaemic control protocol to achieve glycaemic levels in a range of 140-180mg/dl. Main variables analysed were: proportion of glycaemic tests in the target range, proportions of severe hypoglycaemia (under 40mg/dl) and hyperglycaemia over 200mg/dl. RESULTS: We analysed 7864 glycaemic tests from 125 patients, 66 pre-intervention and 59 post-intervention. Average age was 66.24±13.99 years, 64% of patients were male. The proportion of tests within the target range was higher in the intervention group (38.82 vs. 44.34 p<.001). Only one case of severe hypoglycaemia was identified, which happened in the pre-intervention period. The rate of severe hyperglycaemia was lower in the post-intervention group (19.19 vs. 16.28 p=.001). CONCLUSIONS: Our experience shows that implementation of evidence-based interventions can improve glycaemic control during critical illness. We found higher glycaemia levels in the target range. The protocol proved useful in the prevention of severe hypoglycaemia. Nurse-led interventions based on clinical data improved health results in our patients.
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Cuidados Críticos/métodos , Hiperglucemia/prevención & control , Anciano , Protocolos Clínicos , Medicina Basada en la Evidencia , Femenino , Humanos , Hiperglucemia/etiología , Masculino , Estudios Prospectivos , Estrés Fisiológico , Resultado del TratamientoRESUMEN
Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease-control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans.
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Negro o Afroamericano/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Clorhidrato de Erlotinib , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Farmacogenética , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/farmacocinéticaRESUMEN
Racial and ethnic disparities in the pathogenesis of common malignancies and outcomes from treatment remain a major health concern. Factors attributed to these disparities include differences in lifestyle, environment, genetics, and tumor biology. As we strive to personalize cancer therapy, it will be imperative that we understand the relative contributions of each factor so that we may apply this knowledge in choosing the best treatment for each individual, regardless of his or her racial or ethnic heritage.
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Etnicidad/estadística & datos numéricos , Neoplasias/terapia , Grupos Raciales/estadística & datos numéricos , Femenino , Disparidades en el Estado de Salud , Humanos , Estilo de Vida , Masculino , Neoplasias/etnología , Neoplasias/patología , Medicina de Precisión , Resultado del TratamientoRESUMEN
PURPOSE: Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer and is the most common cause of cancer death in industrialized countries. Epigenetic modifications are observed universally during the tumorigenesis of lung cancer. The development of epigenetic-modulating agents utilizing the synergism between hypomethylating agents and histone deacetylase (HDAC) inhibitors provides a novel therapeutic approach in treating NSCLC. METHODS: We performed a phase I trial combining 5-aza-2'-deoxycytidine (decitabine) and valproic acid (VPA), in patients with advanced stage NSCLC. Patients were treated with escalating doses of decitabine (5-15 mg/m(2)) IV for 10 days in combination with VPA (10-20 mg/kg/day) PO on days 5-21 of a 28-day cycle. Pharmacokinetic and pharmacodynamic analysis included decitabine pharmacokinetics and fetal hemoglobin expression. RESULTS: Eight patients were accrued to this phase I study. All patients had advanced NSCLC and had received prior chemotherapy. Eastern Cooperative Oncology Group performance status was 0-2. Major toxicities included myelosuppression and neurotoxicity. Dose-limiting toxicity was seen in two patients suffering grade 3 neurotoxicity during cycle one including disorientation, lethargy, memory loss, and ataxia at dose level 1. One patient had grade 3 neutropenia at the de-escalated dose. No objective response was observed, and stable disease was seen in one patient. Fetal hemoglobin levels increased after cycle one in all seven patients with evaluable results. CONCLUSIONS: We observed that decitabine and valproic acid are an effective combination in reactivating hypermethylated genes as demonstrated by re-expressing fetal hemoglobin. This combination in patients with advanced stage IV NSCLC, however, is limited by unacceptable neurological toxicity at a relatively low dosage. Combining hypomethylating agents with alternative HDAC inhibitors that lack the toxicity of VPA should be explored further.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/patología , Decitabina , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Resultado del Tratamiento , Ácido Valproico/administración & dosificaciónRESUMEN
Mesothelioma is an uncommon malignancy whose global incidence continues to rise. The therapeutic standard for advanced disease is intravenous pemetrexed and cisplatin. The anti-folate capecitabine is significantly less effective than pemetrexed. The balance between thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) is critical to the efficacy of capecitabine. DNA from mesothelioma cell lines was bisulfite treated and examined by MS-PCR, RNA was obtained for real-time PCR analysis, and protein lysates were obtained for Western immunoblot analysis. Cytotoxicity was assessed by MTT assay, comparing 5-aza-CdR pretreated or untreated cells with 5'-deoxy-5-fluorouridine (DFUR), 5-FU, and pemetrexed. Finally bisulfite sequencing of the extracellular growth factor-1 (ECGF-1) gene was performed on 4 mesothelioma samples and pericardial tissue. One of the four cell lines tested (H290) was methylated for ECGF-1. This corresponded to a lack of TP expression by real-time PCR and Western immunoblot. Treatment with 1muM 5-aza-CdR increased TP mRNA and protein expression in H290. DFUR, the substrate for TP, showed increased cytotoxicity when delivered after 5-aza-CdR exposure in the methylated cell line. There was no difference in any of the unmethylated cell lines when cells were exposed to 5-FU or pemetrexed with or without 5-aza-CdR. Patient tumor samples revealed an increased number of methylated CpG sites in ECGF-1 compared to normal pericardium. Methylation of ECGF-1, leads to transcriptional silencing of TP and may explain the lack of any effect of capecitabine, especially when compared to pemetrexed.
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Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Fluorouracilo/análogos & derivados , Antagonistas del Ácido Fólico/farmacología , Mesotelioma/genética , Pericardio/metabolismo , Timidina Fosforilasa/genética , Capecitabina , Línea Celular Tumoral , Islas de CpG , Metilación de ADN , Desoxicitidina/farmacología , Fluorouracilo/farmacología , Glutamatos/farmacología , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Pemetrexed , Regiones Promotoras Genéticas , Análisis de Secuencia de ADNRESUMEN
El dolor es un síntoma muy prevalente en hemodiálisis, pero pasa frecuentemente inadvertido. Los escasos estudios sobre el dolor en diálisis hacen únicamente referencia al dolor crónico. Para conocer las características del dolor intradiálisis y las del dolor crónico fuera de diálisis, se administraron diversas escalas de medición validadas, a un grupo de 27 pacientes en hemodiálisis: la Escala Visual Analógica, el Pain Management Index, el McGill Pain Questionnaire, y el Brief Pain Inventory, primero durante la sesión y posteriormente fuera de la misma. La etiología más frecuente del dolor intradiálisis fue la de tipo isquémico, y la del dolor crónico el musculo esquelético. La prevalencia del dolor intradiálisis fue mayor. El valor medio de la escala visual analógica fue ligeramente superior en el dolor intradiálisis. El valor medio del Pain Management Index fue superior en el dolor crónico. El McGill Pain Questionnaire mostró valores similares en ambas situaciones. Sólo en el dolor crónico el tiempo de permanencia en diálisis se relacionaba con la escala visual, el índice cualitativo total y el número de palabras escogidas, y los niveles de PTHi con la escala visual y la interferencia con el desplazamiento. Recibieron analgesia el 11% de pacientes para el dolor intradiálisis, y el 74% para el dolor crónico. Se concluye que el dolor en diálisis es muy frecuente y su manejo resulta inadecuado, y que las escalas utilizadas se han mostrado útiles para evaluar el dolor en diálisis. Respecto al dolor intradiálisis, el dolor crónico se muestra menos prevalente e intenso, mejor tratado, mayoritariamente de origen musculo esquelético y relacionado con el tiempo en diálisis y el hiperparatiroidismo (AU)
Pain in haemodialysis is very common, although frequently underdiagnosed. Chronic pain in dialysis has been scarcely evaluated, and intradialytic pain has not been specifically analyzed. Our aim was to compare intradialytic versus chronic pain characteristics in the same group of twenty-seven hemodialyzed patients, to investigate whether there were or not differences between them. Several validated scales were used: a) Analogical Visual Scale, defines pain intensity from 0, no pain, to 10,the worst pain; b) Pain Management Index, that results from subtracting pain level from analgesic use, ranging from 3 (inadequate) to + 3 (adequate management); c) McGill Pain Questionnaire, which defines three items: pain related qualitative index, number of words chosen, and present pain intensity; and d) Brief Pain Inventory, which analyses influence of pain inpatients life, was only aplicable to evaluate chronic pain. Tests were administered firstly during the dialysis session for evaluating intradialytic pain, and another day out of the session to evaluate chronic pain. Ischemic pain was the most common during the session (37%), whereas muscle-skeletal was more frequent out of the session (77%). Prevalence of pain was higher during the session (92.5% vs 77.7%, p <0.05). Number of weekly sessions with pain was 1.78 ± 1.2. Analogical visual score was slightly higher during the session with respect to chronic pain (3.28 ± 2.22 vs 2.67 ± 2.13, p = NS). Pain Management Index scores were significantly different (intradialytic: -0.81 ±0.76, chronic pain: -0.12 ± 0.94). McGill test scores were similar in both situations. Only in chronic pain, time on dialysis correlated significantly with analogical visual scores, pain related index and number of words chosen, and parathyroid hormone levels with analogical visual scores and interference to displacement score from Brief Pain Inventory. Farmacological (..) (AU)
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Humanos , Diálisis Renal/efectos adversos , Dolor/epidemiología , /métodos , Analgésicos/uso terapéutico , Epidemiología Descriptiva , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE: Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS: Initially, patients received MMC on day 1 and irinotecan on days 2, 8, 15 and 22, every 6 weeks. MMC dose was fixed at 6 mg/m(2) and cumulative doses of >36 mg/m(2) were not permitted. Irinotecan was escalated in 25 mg/m(2) increments. Due to late-onset diarrhea, the schedule was subsequently shortened to 4 weeks, omitting irinotecan on days 15 and 22. In the second part of the study, celecoxib 400 mg orally twice daily was added to irinotecan/MMC regimen. Potential pharmacokinetic interactions and Topo-1 and DT-diaphorase (NQ01) gene expressions in peripheral-mononuclear cells were evaluated. RESULTS: Forty-five patients were enrolled. Irinotecan 125 mg/m(2) on days 2 and 8 in combination with MMC 6 mg/m(2) on day 1 every 4 weeks is recommended for future studies; myelosuppression and diarrhea are dose-limiting. The addition of celecoxib resulted in unacceptable toxicities despite reductions on irinotecan's dose. No relevant pharmacokinetic interactions occurred between irinotecan and MMC, and mean increases in Topo-1, were observed. Sixteen of 36 patients evaluable for response-assessment had discernable anti-tumor activity, including 1 complete, 4 partial, 10 minor and 1 tumor marker response. Four patients had prolonged (>4 months) disease-stability (stable disease, not included in CR or PR). Patients experiencing complete and partial responses had higher increments in Topo-1 expression. CONCLUSIONS: Modulation of irinotecan by MMC is feasible, devoid of pharmacological interactions and active in solid malignancies. The lack of improvement in therapeutic index does not support the addition of celecoxib.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Celecoxib , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mitomicina/efectos adversos , Mitomicina/farmacocinética , Neoplasias/metabolismo , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients received paclitaxel (Taxol) (200 mg/m(2)) and carboplatin (area under the concentration-time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10-50 microM. RESULTS: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 microM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for > or =4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for > or =4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M). CONCLUSIONS: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Femenino , Factor 1 de Crecimiento de Fibroblastos/sangre , Factor 2 de Crecimiento de Fibroblastos/sangre , Humanos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Suramina/administración & dosificación , Suramina/efectos adversos , Suramina/farmacocinéticaRESUMEN
BACKGROUND: Fenretinide is a semi-synthetic retinoid that has pro-apoptotic effects as a single agent and synergistically with chemotherapy in vitro. We performed this study to determine the toxicity of cisplatin, paclitaxel and fenretinide in patients with advanced cancer, the recommended phase II dose of these agents together, and the pharmacokinetics (PK) of fenretinide when administered with chemotherapy. PATIENTS AND METHODS: Fourteen patients (mean age 57.3) were assessable for pharmacokinetics, toxicity and response. Fenretinide was given orally in 2 divided daily doses for 7 days, starting 24 hours prior to cisplatin and paclitaxel. Cisplatin and paclitaxel were given in standard fashion. Cycles were repeated every 3 weeks. Cycle one fenretinide PK was obtained on days 2 and 8. RESULTS: Dose limiting toxicity (Gr 3 diarrhea and Gr 4 neutropenia) was encountered in two patients during cycle one at 80/175/1,800 mg/m(2) of cisplatin/paclitaxel/fenretinide (dose level 2), respectively. Seven patients received 2-8 cycles at the recommended level of 60/135/1,800 (dose level 1). Severe cumulative toxicities included fatigue, nausea/vomiting, neuropathy, and dehydration. Two patients had a partial response and 4 patients had stable disease for up to 8 cycles. PK analysis demonstrated a reduction in fenretinide Cmax on day 8 compared to day 2, accompanying a decrease in AUC. CONCLUSIONS: Cisplatin/paclitaxel/fenretinide can be administered safely at 60/135/1,800 mg/m(2) respectively on an every three-week schedule. This combination may have activity in a variety of tumors, however, the number of pills required complicates oral dosing of fenretinide, and limits the applicability of this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Femenino , Fenretinida/administración & dosificación , Fenretinida/efectos adversos , Fenretinida/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversosRESUMEN
Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.
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Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Carcinoma/genética , Inhibidores Enzimáticos/farmacología , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias de la Mama/patología , Carcinoma/patología , Análisis Mutacional de ADN , Genes BRCA1 , Genes BRCA2 , Humanos , Neoplasias Pulmonares/patología , Células del EstromaRESUMEN
PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin and paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The treatment regimen was given as defined in a phase I investigation in patients with previously treated ovarian cancer. It consisted of paclitaxel 175 mg/m(2) (1-h infusion) and oxaliplatin 130 mg/m(2) (2-h infusion) given every 21 days. Eligible patients had stage IIIB (pleural effusion)/IV NSCLC, measurable disease, no prior chemotherapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic function. RESULTS: A total of 38 patients were enrolled with the following characteristics: 29% male (n = 11); 71% female (n = 27); median age 64.5 years (range 37-78); performance status of 0-1 84% (n = 32); stage IIIB 8% (n = 3); stage IV 92% (n = 35). One hundred and eighty-one cycles were administered, with a median of four per patient (range one to 12). The overall objective response rate for all 38 patients was 34.2% [95% confidence interval (CI) 19.6% to 51.4%]. This response rate includes 13 patients who met criteria for a partial response. No complete responses were observed. Median overall survival time was 9.2 months (95% CI 6-12.4) and median progression-free survival time was 4.3 months (95% CI 2.1-6.5). The 1- and 2-year overall survival rates were 37% and 21%, respectively. Hematological toxicity included six patients with grade 4 neutropenia. Non-hematological toxicity consisted mainly of grades 1 and 2 neurosensory toxicity. Laryngodysesthesia was observed in two patients following oxaliplatin infusion. No grade 4 non-hematological toxicities were encountered. CONCLUSION: This regimen is well tolerated, and demonstrates activity in patients with advanced NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Paclitaxel/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/patología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Paclitaxel/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Camptothecins are broad-spectrum anticancer drugs that specifically target DNA topoisomerase I (Topo I). The formation of a cleavable drug-Topo I-DNA complex results in lethal double-strand DNA breakage and cell death. However, de novo or acquired clinical resistance to camptothecins is common. Studies of the camptothecin analog irinotecan suggest the following general mechanisms of resistance: (i) variable levels of the enzymes involved in the conversion of irinotecan; (ii) reduced cellular accumulation from active drug efflux; (iii) reduced levels of Topo I expression; (iv) alterations in the structure of Topo I from different mutations; (v) alterations in the cellular response to camptothecin-Topo I-DNA complex formation, which involves proteasome degradation of Topo I and/or enhanced DNA repair; and (vi) activation of the transcription factor nuclear factor kappa B by DNA damage and subsequent suppression of apoptosis. Multiple approaches using pharmacological and biological modulation to circumvent the above mechanisms of resistance have been incorporated into ongoing clinical trials and are expected to enhance the antitumor activity of irinotecan and reduce its systemic toxicity.
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Camptotecina/análogos & derivados , Camptotecina/farmacología , Resistencia a Antineoplásicos , Dosis Máxima Tolerada , FN-kappa B/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Irinotecán , Masculino , FN-kappa B/metabolismo , Neoplasias/diagnóstico , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
No disponible
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Adulto , Femenino , Humanos , Síndromes Mielodisplásicos , Diabetes Insípida , Enfermedades HipotalámicasRESUMEN
In transgenic animal models, the conservation of DNA sequences between the transgene and the host wild-type gene can complicate the evaluation of the expression of each gene. The potential for gene silencing may complicate matters further. Here we report the use of RT-PCR heteroduplex analysis to differentiate the expression of a transgene and its homologous wild-type, even when these genes are very similar in their respective DNA sequences. We designed RT-PCR primers to amplify identically sized 243-bp fragments within the DNA binding domain of the p53 gene from both human and mouse mRNA samples. Ten samples from human p53 (273H) transgenic mice and 10 samples from wild-type controls were tested. Heteroduplex bands were formed in all transgenic samples but were absent from all wild-type samples. In addition, RT-PCR heteroduplex analysis was able in one sample to differentiate a silenced transgene from its wild-type allele, without the assistance of sequencing or labeling. In summary, the RT-PCR heteroduplex analysis is easy to use and has the ability to screen a large number of samples in a short time. The RT-PCR heteroduplex analysis is especially useful for the detection of expression when a transgene and the host homologous endogenous allele are too conserved in sequence to design species-specific RT-PCR primers.
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Animales Modificados Genéticamente/genética , Expresión Génica/genética , Genes p53/genética , Análisis Heterodúplex/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Transgenes/genética , Animales , Secuencia de Bases , Regulación de la Expresión Génica , Humanos , Ratones , Modelos Animales , Datos de Secuencia Molecular , Alineación de Secuencia/métodosRESUMEN
BACKGROUND: Chemorefractory small-cell lung cancer (SCLC) is defined as disease that progresses during primary therapy or within 3 months of completion of primary therapy. Patients with chemorefractory SCLC have a very poor prognosis, and no treatment has been shown to be of significant clinical benefit. Elevated expression of Bcl-2 is found in the majority of SCLCs and has been associated with therapeutic resistance. Suppression of Bcl-2 levels through the use of G3139, an antisense oligonucleotide complementary to the mRNA encoding Bcl-2, might increase the antitumor efficacy of cytotoxic therapy. PATIENTS AND METHODS: Twelve patients with chemorefractory SCLC participated in this pilot trial of paclitaxel combined with G3139. G3139 was given by continuous i.v. infusion over 7 days at a fixed dose of 3 mg/kg/day. Paclitaxel dose was initially 175 mg/m2 on day 6, but was decreased to 150 mg/m2 due to myelosuppression observed in two of the three patients treated in the first dose cohort. RESULTS: The combination of paclitaxel at 150 mg/m2 and G3139 at 3 mg/kg/day was found to be feasible and well tolerated. No objective responses were observed, but two patients had stable disease, one remaining stable on therapy for >30 weeks. Plasma G3139 levels were determined, and were found to be highest in the patient with prolonged stable disease, suggesting that individual variation in metabolism and clearance of the antisense oligonucleotide may influence activity. CONCLUSIONS: This study demonstrates that G3139 can be combined with paclitaxel in a cytotoxic dose range, and suggests that a similar combination be tested for activity in the context of chemoresponsive disease.
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Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Oligonucleótidos Antisentido/farmacología , Paclitaxel/farmacología , Tionucleótidos/farmacología , Adulto , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Carcinoma de Células Pequeñas/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Femenino , Genes bcl-2 , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Oligonucleótidos Antisentido/administración & dosificación , Paclitaxel/administración & dosificación , Tionucleótidos/administración & dosificación , Resultado del TratamientoRESUMEN
DNA hypermethylation of CpG islands in the promoter region of genes is associated with transcriptional silencing. Treatment with hypo-methylating agents can lead to expression of these silenced genes. However, whether inhibition of DNA methylation influences the expression of unmethylated genes has not been extensively studied. We analysed the methylation status of CDKN2A and CDKN2D in human lung cancer cell lines and demonstrated that the CDKN2A CpG island is methylated, whereas CDKN2D is unmethylated. Treatment of cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), an inhibitor of DNA methyltransferase 1, induced a dose and duration dependent increased expression of both p16(INK4a) and p19(INK4d), the products of CDKN2A and CDKN2D, respectively. These data indicate that global DNA demethylation not only influences the expression of methylated genes but also of unmethylated genes. Histone acetylation is linked to methylation induced transcriptional silencing. Depsipeptide, an inhibitor of histone deacetylase, acts synergistically with 5-Aza-CdR in inducing expression of p16(INK4a) and p19(INK4d). However, when cells were treated with higher concentrations of 5-Aza-CdR and depsipeptide, p16(INK4a) expression was decreased together with significant suppression of cell growth. Interestingly, p19(INK4d) expression was enhanced even more by the higher concentrations of 5-Aza-CdR and depsipeptide. Our data suggest that p19(INK4d) plays a distinct role from other INK4 family members in response to the cytotoxicity induced by inhibition of DNA methylation and histone deacetylation.
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Azacitidina/análogos & derivados , Azacitidina/farmacología , Proteínas de Ciclo Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/genética , Regiones Promotoras Genéticas/genética , Southern Blotting , Western Blotting , Supervivencia Celular/efectos de los fármacos , Islas de CpG/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p19 de las Quinasas Dependientes de la Ciclina , Metilasas de Modificación del ADN/metabolismo , Decitabina , Silenciador del Gen , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , ARN Mensajero/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), which catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra of activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on an intermittent schedule in combination with paclitaxel in previously-treated patients with locally advanced or metastatic breast cancer. The study also sought to recommend doses for subsequent disease-specific studies, identify clinically significant pharmacokinetic interactions, and detect preliminary antitumor activity. PATIENTS AND METHODS: Nineteen previously treated women with metastatic breast cancer whose prior treatment included neither paclitaxel or capecitabine received one hundred one courses of capecitabine and paclitaxel. Paclitaxel was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m2 and capecitabine was administered as 2 divided daily doses for 14 days followed by a seven-day rest period every 3 weeks. The dose of capecitabine was increased from a starting dose of 1650 mg/m2/d. The plasma sampling scheme in the first course permitted characterization of the pharmacokinetics of each agent given alone and concurrently to detect major pharmacokinetic interactions. RESULTS: Palmar plantar erythrodysesthesia (hand foot syndrome) and neutropenia were the principal dose-limiting toxicities (DLT). Other toxicities included diarrhea and transient hyperbilirubinemia. Three of eight new patients treated with capecitabine 2000 mg/m2/d and paclitaxel 175 mg/m2 experienced DLT in the first course, whereas none of eleven new patients treated with capecitabine 1650 mg/m2/d and paclitaxel 175 mg/m2 developed DLT. Pharmacokinetic studies indicated that capecitabine did not grossly affect the pharmacokinetics of paclitaxel, and there were no major effects of paclitaxel on the pharmacokinetics of capecitabine and capecitabine metabolites. However, AUC values for the major 5-FU catabolite, fluorobeta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complete and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was previously treated with high-dose chemotherapy and hematopoietic stem-cell support had major responses. Seven of nineteen patients had stable disease as their best response. CONCLUSIONS: Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Administración Oral , Adulto , Área Bajo la Curva , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/análogos & derivados , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinéticaRESUMEN
PURPOSE: To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. RESULTS: Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m(2)/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m(2)/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m(2)/d dose level. At the 18-mg/m(2)/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary myopathic process. A patient with a platinum- and taxane-resistant papillary serous carcinoma of the peritoneum experienced a partial response lasting 22 months. Pharmacokinetics were dose-independent, optimally described by a three-compartment model, and there was modest drug accumulation over the 5 days of treatment. CONCLUSION: Although no dose-limiting events were noted in the first two courses of LU79553, cumulative muscular toxicity precluded repetitive treatment with LU79553 at doses above 18 mg/m(2)/d, which is the recommended dose for subsequent disease-directed evaluations. The preliminary antitumor activity noted is encouraging, but the qualitative and cumulative nature of the principal toxicities, as well as the relatively small number of patients treated repetitively, mandate that rigorous and long-term toxicologic monitoring be performed in subsequent evaluations of this unique agent.
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Amidas/efectos adversos , Amidas/farmacocinética , Sustancias Intercalantes/efectos adversos , Sustancias Intercalantes/farmacocinética , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Amidas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Sustancias Intercalantes/uso terapéutico , Isoquinolinas/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedades Musculares/inducido químicamente , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
OBJECTIVES: This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule. PATIENTS AND METHODS: CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G). RESULTS: Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2. CONCLUSIONS: When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.