RESUMO
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.
Assuntos
Proteína BRCA1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ligação a DNA/biossíntese , Endonucleases/biossíntese , Neoplasias Pulmonares/genética , Rad51 Recombinase/biossíntese , Adulto , Idoso , Biópsia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA , Reparo do DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Análise de SobrevidaRESUMO
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.
Assuntos
Antineoplásicos/metabolismo , Regulação Enzimológica da Expressão Gênica , Neoplasias/tratamento farmacológico , Farmacogenética , Polimorfismo Genético , Pirimidinas/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/enzimologia , Neoplasias/metabolismoRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Taxoides/efeitos adversosRESUMO
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.
Assuntos
Amifostina/uso terapêutico , Desoxicitidina/análogos & derivados , Epirubicina/efeitos adversos , Mucosa Bucal/efeitos dos fármacos , Estomatite/prevenção & controle , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/administração & dosagem , Epirubicina/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Dor/etiologia , Estomatite/induzido quimicamente , Resultado do Tratamento , GencitabinaRESUMO
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.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Cistite/induzido quimicamente , Esquema de Medicação , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Polivinil/administração & dosagemRESUMO
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 Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
, Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
, Desoxicitidina/análogos & derivados
, Neoplasias Pulmonares/tratamento farmacológico
, Adenocarcinoma/tratamento farmacológico
, Adenocarcinoma/patologia
, Adenocarcinoma/secundário
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
, Carcinoma de Células Grandes/tratamento farmacológico
, Carcinoma de Células Grandes/patologia
, Carcinoma de Células Grandes/secundário
, Carcinoma Pulmonar de Células não Pequenas/patologia
, Carcinoma de Células Escamosas/tratamento farmacológico
, Carcinoma de Células Escamosas/patologia
, Carcinoma de Células Escamosas/secundário
, Cisplatino/administração & dosagem
, Desoxicitidina/administração & dosagem
, Epirubicina/administração & dosagem
, Feminino
, Humanos
, Neoplasias Pulmonares/patologia
, Masculino
, Pessoa de Meia-Idade
, Estadiamento de Neoplasias
, Prognóstico
, Qualidade de Vida
, Taxa de Sobrevida
, Resultado do Tratamento
, Gencitabina