RESUMO
We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Alopecia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Diarreia/induzido quimicamente , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neutropenia/induzido quimicamente , Análise de Sobrevida , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
On the basis of epidemiological data, an association between Chlamydia pneumoniae (Cp) infection and head and neck cancer might be suggested. The aim of the present study was to detect Cp-DNA within tumour tissue specimens by a two-step polymerase chain reaction. Investigation was planned on the Fleming's procedure for early termination when initial results were extreme. So, after ten consecutive patients, only one tumour contained Cp-DNA. Hence the prevalence could be regarded as inferior to 60% (2a=b=0.08), the threshold under which a direct role of Cp in head and neck cancer development does not seem to be likely.
Assuntos
Carcinoma de Células Escamosas/microbiologia , Infecções por Chlamydophila/complicações , Chlamydophila pneumoniae/genética , Neoplasias de Cabeça e Pescoço/microbiologia , Pneumonia Bacteriana/complicações , Idoso , Carcinoma de Células Escamosas/epidemiologia , Infecções por Chlamydophila/epidemiologia , DNA Bacteriano/análise , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/epidemiologia , PrevalênciaRESUMO
The role of p53 in apoptosis and the contrasting p53 status in tumors prompted us to investigate the bleomycin-induced apoptosis in p53-null human leukemia HL-60 cells (bleomycin at 160 microM for 7.5 h). Cells with apoptotic phenotype increased from 0.87% in controls to 9.40% in bleomycin-treated cells. Both the enzymes, caspase-3 and -8, were activated. Furthermore, the apoptotic phenotypes totally disappeared with zVAD-fmk, a caspase inhibitor. Besides, cytochrome c release from mitochondria happened simultaneously to apoptotic phenotypes, shrinkage of mitochondria but being independent of the mitochondrial permeability transition, since cyclosporine A and bongkrekic acid were inefficient on induced apoptosis. On the other hand, incubations with bleomycin (BLM) did not result in detectable changes in the expression of Bcl-2- and Bax-mRNA neither Bcl-2- or Bax-proteins. In conclusion, we suggest that BLM can produce apoptosis independently of p53 through three mechanisms: i) at the nuclear level by its endonuclease activities; ii) at the cell membrane, by activating caspases; and iii) at the mitochondria by releasing cytochrome c. These results indicate that BLM-induced apoptosis in HL-60 cells results from the activation of a mitochondria-dependent caspase cascade which includes also the activation of the initiator caspase-8.
Assuntos
Apoptose , Bleomicina/farmacologia , Genes p53 , Leucemia/tratamento farmacológico , Leucemia/patologia , Clorometilcetonas de Aminoácidos/farmacologia , Antimetabólitos Antineoplásicos/farmacologia , Western Blotting , Ácido Bongcréquico/farmacologia , Caspase 3 , Caspase 8 , Caspases/biossíntese , Caspases/metabolismo , Linhagem Celular , Ciclosporina/farmacologia , Citocromos c/metabolismo , Fragmentação do DNA , Ativação Enzimática , Células HL-60 , Humanos , Microscopia Eletrônica , Mitocôndrias/patologia , Fenótipo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2RESUMO
The subunit composition of nicotinic acetylcholine receptors involved in apoptosis is an ongoing question. HL-60 cells were used in order to investigate the implication of nicotinic acetylcholine receptors in bleomycin-induced apoptosis. We found that bleomycin-induced apoptosis was significantly enhanced by nicotine and was blocked by nicotinic acetylcholine receptor antagonists, including alpha-bungarotoxin, a competitive antagonist of alpha 7 nicotinic receptor. Among the other agonists tested, 3-[2,4-dimethoxybenzylidene]anabaseine (GTS-21)-selective agonist for alpha 7-nicotinic acetylcholine receptor-, but not epibatidine or cytisine, enhanced bleomycin-induced apoptosis. In addition to these results, the detectable presence of alpha 7-mRNA supports a key role of alpha 7-nicotinic acetylcholine receptors in the modulation of the induced apoptosis by nicotine.
Assuntos
Apoptose/fisiologia , Receptores Nicotínicos/fisiologia , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Nicotina/farmacologiaRESUMO
The Bleomycin (BLM)-induced apoptosis in peripheral blood mononuclear cells (PBMC), from patients with advanced squamous cell carcinoma of the head and neck (SCCHN), cultured in vitro with PHA, was tested as a predictive indicator of the survival time. The rates of the PBMC BLM-induced apoptosis and of the cycling-PBMCs, measured respectively after Giemsa- and Feulgen-staining were determined in 25 patients before induction chemotherapy. By using the Cox model, the survival probability was significantly and independently increased for a high percentage of PBMC BLM-induced apoptosis and a high rate of cycling PBMCs. (Chi-2(2): 10; p=0.007). Six patients, in whom both PBMC variables were simultaneouly greater than the median values, showed a median survival time as long as 60 months versus 10 months for the other 19. Conclusively, the PBMC susceptibility to BLM-induced apoptosis as well as the PBMC capability for cycling may be regarded as independent pretherapeutic prognosis factors for patients with advanced SCCHN.