RESUMO
The first patient, a 68-year-old woman, presented neutropenic fever and hemorrhagic diarrhea on the sixth day of a combination chemotherapy of carboplatin and paclitaxel. The second patient, a 30-year-old man, presented neutropenia and diarrhea on the tenth day of the second cycle of a combination chemotherapy of cisplatin and vinorelbine. In both patients, abdominal computed tomography scan showed thickening of the colon wall and pericolic edema, and the ultrasonography revealed echogenic thickening of the colon walls. These findings confirmed the diagnosis of neutropenic enterocolitis. After the treatments, we changed the anticancer drug regimen; and successfully achieved partial responses.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/efeitos adversos , Enterocolite Neutropênica/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Colo/diagnóstico por imagem , Enterocolite Neutropênica/diagnóstico , Enterocolite Neutropênica/tratamento farmacológico , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
BACKGROUND: We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance. In order to extend this result to the clinical setting, it is important to elucidate the role of SN-38 glucuronidation by UGT1A isoforms in CPT-11/SN-38 resistance in vivo. MATERIALS AND METHODS: We examined SN-38 glucuronidation activity in COS-7 cells transfected with full-length cDNAs for human UGT isoforms (UGT1A1, UGT1A3, UGT1A6 and UGT1A10). The gene expression levels of UGT isoforms were examined in lung cancer cell lines and 14 lung cancer samples by semi, quantitative RT-PCR. RESULTS: Our HPLC assay results showed that both UGT1A1 and UGT1A10 are responsible for SN-38 glucuronidation. The levels of UGT1A1 and UGT1A10 expression in a CPT-11/SN-38-resistant cell line were increased compared to levels in the parent cell line. Furthermore, there was considerable intersubject variability in 14 lung cancer samples, but UGT1A1 and UGT1A10 expression levels were significantly correlated (r=0. 70, p=0.004). Our results suggest that not only UGT 1A1, but also UGT 1A10, plays an important role in detoxifying CPT-11/SN-38, leading to resistance to CPT-11/SN-38 in lung cancer.
Assuntos
Antineoplásicos Fitogênicos/metabolismo , Camptotecina/análogos & derivados , Camptotecina/biossíntese , Camptotecina/metabolismo , Glucuronídeos/biossíntese , Glucuronosiltransferase/metabolismo , Neoplasias Pulmonares/enzimologia , Idoso , Idoso de 80 Anos ou mais , Animais , Células COS , Camptotecina/farmacologia , Chlorocebus aethiops , Cromatografia Líquida de Alta Pressão , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica , Glucuronídeos/metabolismo , Glucuronídeos/farmacologia , Glucuronosiltransferase/biossíntese , Glucuronosiltransferase/genética , Humanos , Irinotecano , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-IdadeRESUMO
We previously developed limited-sampling models (LSM) for estimation of the area under the concentration curve (AUC) of free carboplatin (Anticancer Res 17: 4571-4576, 1997). The one-point model was: AUC (mg/ml x min) = 0.93 x C3h + 0.47 and the two-point model was: AUC (mg/ml x min) = 0.16 x C1h + 2.26 x C8h + 0.75, in which C3h, C1h and C8h represented the plasma concentration, sampled at 3 h, 1 h and 8 h after the start of a 1-h carboplatin infusion, respectively. In this study, we tried to confirm the utility of our LSMs in combination chemotherapy with taxanes. We obtained 29 data series from 29 patients who received carboplatin in combination with docetaxel (n = 16) or paclitaxel (n = 13). The actual AUC was strongly correlated with the AUC calculated from both one- and two-point models (one-point model; the mean prediction error (MPE) = -4.44 +/- 2.15%, the root mean squared error (RMSE) = 12.22 +/- 0.84%, two-point model; MPE = -1.89 +/- 1.66%, RMSE = 8.99 +/- 0.81%). Our LSMs proved to be unbiased and precise and are also useful for calculating carboplatin AUC in combination with taxanes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Paclitaxel/farmacocinética , Taxoides/farmacocinética , Idoso , Área Sob a Curva , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Docetaxel , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Reprodutibilidade dos Testes , Taxoides/administração & dosagemRESUMO
We conducted a clinical pharmacological evaluation of paclitaxel/carboplatin combination in Japanese patients with non-small cell lung cancer. The purpose of this study was to identify the optimal dose of this combination and to investigate the relationships between the pharmacokinetic profiles of these 2 drugs, serum thrombopoietin (TPO) kinetics and the platelet-sparing effect. Patients received paclitaxel at 180-225 mg/m(2) by intravenous infusion over 3 h, followed by carboplatin at a target area under the concentration-time curve (AUC) of 6 mg/ml x min as a 1-h infusion. Serum paclitaxel, free platinum and TPO concentrations were measured using high-performance liquid chromatography, atomic absorption spectrometry and a double-sandwich enzyme-linked immunosorbent assay, respectively. Thirteen patients were enrolled. Neutropenia was the most frequent hematological toxicity and was significantly related to the time for which paclitaxel concentrations remained above 0.05 micro mol/ml. The prominent non-hematological toxicities were myalgia and sensory-dominant neuropathy. In this study, platelet and serum TPO kinetics were clearly different from those in our previous study of single-agent carboplatin (21). The platelet counts at the nadir were significantly higher (p<0.0001) in patients treated with paclitaxel/carboplatin combination (161,000+/-38,000/ micro l) compared with single-agent carboplatin (92,000+/-28,000/ micro l). The early increase in TPO (the percentage increase in TPO at day 4) was significantly greater (p=0.0345) in patients treated with paclitaxel/carboplatin combination (57.8+/-44.5%) compared with single-agent carboplatin (21.3+/-34.1%). The recommended doses are paclitaxel 210 mg/m(2) and carboplatin at an AUC of 6 mg/ml x min every 3 weeks. The observed platelet-sparing effect of the paclitaxel/carboplatin might be related to the early increase in circulating TPO levels, although the precise mechanism remains to be elucidated.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Plaquetas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Trombopoetina/sangue , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Cinética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Espectrofotometria AtômicaRESUMO
We present a case of a 39-year-old woman with sporadic tuberous sclerosis (TSC), whose chest radiograph demonstrated bilateral diffuse nodular shadowing. A transbronchial lung biopsy specimen revealed the possibility of multiple atypical adenomatous hyperplasia (AAH), which had not been reported in TSC. Thoracoscopic lung biopsy was, therefore, performed. The specimens revealed the characteristic histological and immunohistochemical features of micronodular pneumocyte hyperplasia, which has been reported as an extremely rare pulmonary manifestation of TSC. In addition, no evidence of AAH or any other pulmonary involvements of TSC including lymphangioleiomyomatosis were detected in biopsy specimens obtained at thoracoscopy.