RESUMEN
Aim of this explorative study was to determine the prognostic value of protein expression of the DNA damage repair enzymes ERCC1, hRad51, and BRCA1 for tumour response and survival of non-small-cell lung cancer patients treated with chemotherapy. Patients with either a short or long overall survival were selected from a randomized phase III trial comparing cisplatin-gemcitabine and epirubicin-gemcitabine. Tumour biopsies were assessed for differences in immunohistochemical staining using antibodies against ERCC1, hRad51, and BRCA1. A total of 33 patients were included. A positive nuclear staining for ERCC1, hRad51, and BRCA1 was observed in 44, 12, and 90% of biopsies, respectively. In large cell carcinoma nuclear hRad51 staining was absent. In five biopsies stained for hRad51 an unexpected membrane-like staining was observed; these biopsies showed no nuclear staining. DNA damage repair protein expressions were not significantly different in responders versus non-responders, or in patients with a short or long overall survival. In conclusion, immunohistochemical staining of ERCC1, hRad51, and BRCA1, in tumour biopsies from non-small-cell lung cancer patients was not predictive for tumour response and survival after chemotherapy.
Asunto(s)
Proteína BRCA1/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas de Unión al ADN/biosíntesis , Endonucleasas/biosíntesis , Neoplasias Pulmonares/genética , Recombinasa Rad51/biosíntesis , Adulto , Anciano , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Daño del ADN , Reparación del ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Análisis de SupervivenciaRESUMEN
Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumour-specific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5'-nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.
Asunto(s)
Antineoplásicos/metabolismo , Regulación Enzimológica de la Expresión Génica , Neoplasias/tratamiento farmacológico , Farmacogenética , Polimorfismo Genético , Pirimidinas/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/enzimología , Neoplasias/metabolismoRESUMEN
Response rate and toxicity of second-line therapy with docetaxel (75 mg m(-2)) or docetaxel, irinotecan, and lenogastrim (60 mg m(-2), 200 mg m(-2), and 150 microg m(-2) day(-1), respectively) were compared in 108 patients with stage IIIb-IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Taxoides/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Taxoides/efectos adversosRESUMEN
BACKGROUND: Intravenous administration of amifostine reduces chemotherapy-induced toxicity. Preclinical experiments showed a reduction in radiation-induced mucositis after local application of the active metabolite of amifostine (WR-1065). This study evaluated the effect of local application of WR-1065 on chemotherapy-induced oral mucositis. PATIENTS AND METHODS: Non-small cell lung cancer patients treated with gemcitabine and epirubicin every 3 weeks for a maximum of five cycles were included. WR-1065 was administered during the second and third cycle as an oral rinse. Oral mucositis evaluation included WHO toxicity grading, a validated oral mucositis assessment scale (OMAS) and a questionnaire. RESULTS: Twenty-four patients were evaluated for at least one control and one rinse cycle. Mucositis scores, pain and feeding difficulties increased from day 1 to day 15, and were not significantly different between the control and rinse cycles. Local application of WR-1065 leads to detectable quantities of WR-1065 in epithelial mucosa cells. A negative correlation between the WR-1065 concentration and OMAS score was found. CONCLUSION: No clinical detectable influence of WR-1065 on oral mucositis was found.
Asunto(s)
Amifostina/uso terapéutico , Desoxicitidina/análogos & derivados , Epirrubicina/efectos adversos , Mucosa Bucal/efectos de los fármacos , Estomatitis/prevención & control , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Desoxicitidina/administración & dosificación , Epirrubicina/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mucosa Bucal/patología , Dolor/etiología , Estomatitis/inducido químicamente , Resultado del Tratamiento , GemcitabinaRESUMEN
In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level (80 mg x m(-2) week(-1)), no dose-limiting toxicities occurred during the first cycle (n=3). Subsequently, three patients were enrolled at the second dose level (120 mg x m(-2) week(-1)). Two of three patients at the 80 mg x m(-2) week(-1) cohort developed haemorrhagic cystitis (grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg x m(-2) week(-1) cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg x m(-2) week(-1), grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg x m(-2) week(-1). Cumulative bladder toxicity was dose-limiting toxicity at 80 mg x m(-2) week(-1). Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias/tratamiento farmacológico , Adulto , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/farmacocinética , Cistitis/inducido químicamente , Esquema de Medicación , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Polivinilos/administración & dosificaciónRESUMEN
The purpose of our study was to compare progression-free survival and quality of life (QOL) after cisplatin-gemcitabine (CG) or epirubicin-gemcitabine (EG) in chemotherapy-naive patients with unresectable non-small-cell lung cancer. Patients (n=240) were randomised to receive gemcitabine 1125 mg x m(-2) (days 1 and 8) plus either cisplatin 80 mg x m(-2) (day 2) or epirubicin 100 mg x m(-2) (day 1) every 3 weeks for a maximum of five cycles. Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
, Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico
, Desoxicitidina/análogos & derivados
, Neoplasias Pulmonares/tratamiento farmacológico
, Adenocarcinoma/tratamiento farmacológico
, Adenocarcinoma/patología
, Adenocarcinoma/secundario
, Adulto
, Anciano
, Anciano de 80 o más Años
, Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
, Carcinoma de Células Grandes/tratamiento farmacológico
, Carcinoma de Células Grandes/patología
, Carcinoma de Células Grandes/secundario
, Carcinoma de Pulmón de Células no Pequeñas/patología
, Carcinoma de Células Escamosas/tratamiento farmacológico
, Carcinoma de Células Escamosas/patología
, Carcinoma de Células Escamosas/secundario
, Cisplatino/administración & dosificación
, Desoxicitidina/administración & dosificación
, Epirrubicina/administración & dosificación
, Femenino
, Humanos
, Neoplasias Pulmonares/patología
, Masculino
, Persona de Mediana Edad
, Estadificación de Neoplasias
, Pronóstico
, Calidad de Vida
, Tasa de Supervivencia
, Resultado del Tratamiento
, Gemcitabina