RESUMEN

We investigated the effects of celecoxib combined with (-)-epigallocatechin-3-gallate (EGCG) or polyphenon E in a cisplatin-induced lung tumorigenesis model. Four-week-old female A/J mice were divided into seven groups: (i) Control, (ii) 150 mg/kg celecoxib (150Cel), (iii) 1,500 mg/kg celecoxib (1500Cel), (iv) EGCG+150 mg/kg celecoxib (EGCG+150Cel), (v) EGCG+1,500 mg/kg celecoxib (EGCG+1500Cel), (vi) polyphenon E+150 mg/kg celecoxib (PolyE+150Cel), and (vii) polyphenon E+1,500 mg/kg celecoxib (PolyE+1500Cel). All mice were administered cisplatin (1.62 mg/kg of body weight, i.p.) 1×/week for 10 weeks and sacrificed at week 30; the numbers of tumors on the lung surface were then determined. The tumor incidence and multiplicity (no. of tumors/mouse, mean±SD) were respectively 95% and 2.15±1.50 in Control, 95% and 2.10±1.29 in 150Cel, 86% and 1.67±1.20 in 1500Cel, 71% and 1.38±1.24 in EGCG+150Cel, 67% and 1.29±1.38 in EGCG+1500Cel, 80% and 1.95±1.36 in PolyE+150Cel, and 65% and 1.05±0.10 in PolyE+1500Cel. The combination of high-dose celecoxib with EGCG or polyphenon E significantly reduced multiplicity in cisplatin-induced lung tumors.

Asunto(s)

Cisplatino , Inhibidores de la Ciclooxigenasa 2 , Animales , Femenino , Ratones , Antiinflamatorios no Esteroideos , Carcinogénesis/inducido químicamente , Celecoxib/farmacología , Celecoxib/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/farmacología , Pulmón

RESUMEN

BACKGROUND: There has been no standard chemotherapy for advanced or recurrent thymic malignancies including thymic carcinoma (TC) and invasive thymoma (IT), though platinum and anthracycline have been reported as effective agents for the treatment of these diseases. The objective of this study was to evaluate the efficacy and safety of the combination of amrubicin (AMR), a new anthracycline agent, and carboplatin (CBDCA) in patients with advanced thymic malignancies. METHODS: Patients with histologically confirmed thymic malignancies received AMR (35 mg/m, days 1-3) and CBDCA (area under the curve 4.0, day 1) every 3 weeks. Patients who had received previous chemotherapy were treated with a reduced dose of AMR (30 mg/m). The primary end point was objective response rate (ORR), and secondary endpoints were progression-free survival, overall survival, and toxicity profile. RESULTS: From December 2008 to October 2012, 51 patients (33 TC and 18 IT) were enrolled. The median number of treatment cycles was four in each group. The ORR and progression-free survival were 30% (95% confidence interval, 14-46) and 7.6 months in the TC group, and 17% (95% confidence interval, 0-34) and 7.6 months in the IT group, respectively. The ORR of TC patients without previous chemotherapy (n = 19) was 42%. Although grade 3 or 4 hematological toxicities were common including neutropenia (82%) and febrile neutropenia (22%), these were transient and manageable. Nonhematological toxicities were moderate and no treatment-related death was observed. CONCLUSIONS: The combination of AMR with CBDCA was active for TC with acceptable toxicity, although it was not effective for IT. Further investigation of this regimen for advanced TC is warranted.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Timoma/tratamiento farmacológico , Neoplasias del Timo/tratamiento farmacológico , Adulto , Anciano , Antraciclinas/administración & dosificación , Carboplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Timoma/patología , Neoplasias del Timo/patología

RESUMEN

Invasive candidiasis has increased as nosocomial infection recently in cancer patients who receive systemic chemotherapy, and the timely risk assessment for developing such specific infection is crucial. Especially in those concomitantly with hypopituitarism, febrile neutropenia with candidiasis can cause severe stress and lead potentially to sudden fatal outcome when the temporal steroid coverage for the adrenal insufficiency is not fully administered. We report a 72-year-old male case diagnosed as non-small-cell lung cancer, Stage IIIA. He had received a steroid replacement therapy for the prior history of hypophysectomy due to pituitary adenoma with hydrocortisone of 3.3 mg/day, equivalent to prednisolone of 0.8 mg/day. This very small dosage of steroid was hardly supposed to weaken his immune system, but rather potentially led to an inappropriate supplementation of his adrenal function, assuming that the serum sodium and chlorine levels decreased. On Day 6 of second cycle of chemotherapy with carboplatin and paclitaxel, he developed sudden febrile neutropenia, septic shock and ileus, leading to death. After his death, the venous blood culture on Day 7 detected Candida albicans. Autopsy findings showed a massive necrotizing enterocolitis with extensive Candida invasion into submucous tissue. In conclusion, this case may suggest that (i) immediate initiation of antifungal therapy soon after the careful risk assessment of Candida infection and (ii) adequate administration of both basal steroid replacement therapy and temporal steroid coverage for febrile neutropenia might have improved his fatal outcome.

Asunto(s)

Corticoesteroides/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Candidemia/etiología , Neutropenia Febril/complicaciones , Hipopituitarismo/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Choque Séptico/microbiología , Adenoma/cirugía , Corticoesteroides/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Candidemia/complicaciones , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Resultado Fatal , Neutropenia Febril/inducido químicamente , Humanos , Hipofisectomía/efectos adversos , Hipopituitarismo/complicaciones , Hipopituitarismo/etiología , Neoplasias Pulmonares/complicaciones , Masculino , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Neoplasias Hipofisarias/cirugía

RESUMEN

A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine-methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors.

RESUMEN

A 32-year-old male with CATCH22 syndrome presented with a high fever and productive cough after taking drugs for acute bronchitis, including (L)-carbocisteine. Chest radiography revealed ground-glass opacities in the bilateral lung fields. He had a history of similar pneumonia. Under the assumption of drug-induced pneumonia, or bacterial or viral pneumonia, all drugs including (L)-carbocisteine were discontinued, and antibiotics were started. A drug-induced lymphocyte stimulation test was positive only for (L)-carbocisteine. The only drug in common between this and the previous episode of pneumonia was (L)-carbocisteine. We thus concluded that this was a definite case of (L)-carbocisteine-induced pneumonia in a patient with CATCH22 syndrome.

Asunto(s)

Antiinfecciosos/efectos adversos , Carbocisteína/efectos adversos , Síndrome de DiGeorge/complicaciones , Hipersensibilidad a las Drogas/etiología , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Adulto , Antibacterianos/uso terapéutico , Antiinfecciosos/uso terapéutico , Carbocisteína/uso terapéutico , Tos/tratamiento farmacológico , Tos/fisiopatología , Síndrome de DiGeorge/diagnóstico , Hipersensibilidad a las Drogas/fisiopatología , Estudios de Seguimiento , Humanos , Masculino , Neumonía/complicaciones , Radiografía Torácica/métodos , Medición de Riesgo , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento

RESUMEN

PARP enzyme plays a key role in the cellular machinery responsible for DNA damage repair. PTEN is a tumor-suppressor gene deactivating PI3K downstream of EGFR signaling. We hypothesize that PTEN-deficient lung cancer cells suppressed DNA damage signaling and that the absence of PTEN can sensitize these cells to a concurrent treatment of a DNA-damaging agent (cisplatin) and a PARP inhibitor (olaparib). To investigate the effect of olaparib and cisplatin on PTEN-deficient lung tumors, two EGFR-mutant (deletion in exon19) non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild-type) and H1650 (PTEN loss), were used. We transfected intact PTEN gene into H1650 cells (H1650(PTEN+)) and knocked down PTEN expression in the PC-9 cells (PC-9(PTEN-)) using short hairpin RNA (shRNA). Combination of cisplatin with olaparib showed a synergistic effect in vitro according to the combination index in H1650 cells. Restoration of PTEN in the H1650 cells decreased sensitivity to the combination. Ablation of PTEN in PC-9 cells increased sensitivity to olaparib and cisplatin. We also examined the effectiveness of cisplatin and olaparib in a xenograft model using H1650 and PC-9(PTEN-) cells. The combination of cisplatin with olaparib was more effective than each agent individually. This effect was not observed in a xenograft model using H1650(PTEN+) and PC-9 cells. Mechanistic investigations revealed that PTEN deficiency caused reductions in nuclear RAD51 and RPA focus formation and phosphorylated Chk1 and Mre11. Thus, genetic inactivation of PTEN led to the suppression of DNA repair.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Fosfohidrolasa PTEN/deficiencia , Ftalazinas/farmacología , Piperazinas/farmacología , Animales , Línea Celular Tumoral , Cisplatino/administración & dosificación , Daño del ADN , Reparación del ADN , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Fosfohidrolasa PTEN/metabolismo , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

PURPOSE: Chemoradiotherapy (CHRT) yields a favorable antitumor activity in patients with limited-stage small-cell lung cancer (LD-SCLC) with a response rate of around 80%. Even in such responders, the majority recur, indicating the importance of identifying a subset of patients with a poor outcome earlier through the treatment. We investigated whether the timing of obtaining tumor regression with the CHRT could affect the prognosis in LD-SCLC patients who finally achieved the objective response through the treatment. PATIENTS AND METHODS: We retrospectively reviewed medical charts of 70 LD-SCLC patients who obtained complete response (CR) or partial response (PR) with the 3 or 4 cycles of first-line CHRT between 1988 and 2006. RESULTS: In the whole 70 patients with CR/PR, the median survival time and median progression free survival (PFS) were 39.6 and 12.3months, respectively. Fifty-two (74.3%) of the 70 patients entered CR/PR after the first cycle of CHRT, and their 2-year survival rates were significantly longer than that in the remaining 18 patients without entering CR/PR yet at the end of first cycle (72.3% and 7.1%, respectively, p<0.001). Cox regression analysis showed that the early response to the treatment was a significant prognostic factors (hazard ratio=0.098; 95% confidence interval=0.036-0.269). Regarding PFS, similar findings were observed. CONCLUSIONS: Patients without entering CR/PR yet after the first course had a poorer outcome even though the objective response was finally confirmed through the treatment. Development of more effective treatments for these high-risk patients is warranted to improve their poor prognosis.

Asunto(s)

Quimioradioterapia , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células Pequeñas/terapia , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Resultado del Tratamiento

RESUMEN

INTRODUCTION: Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time. METHODS: We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis. RESULTS: In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033). CONCLUSIONS: The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.

Asunto(s)

Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Demografía , Humanos , Incidencia , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo

Asunto(s)

Histiocitosis de Células de Langerhans/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Vinblastina/administración & dosificación

RESUMEN

BACKGROUND: In advanced non-small-cell lung cancer (NSCLC), with the increasing number of active compounds available in salvage settings, survival after progression to first-line chemotherapy seems to have improved. A literature survey was conducted to examine whether survival post-progression (SPP) has improved over the years and to what degree SPP correlates with overall survival (OS). METHODS AND FINDINGS: Median progression-free survival (MPFS) time and median survival time (MST) were extracted in phase III trials of first-line chemotherapy for advanced NSCLC. SPP was pragmatically defined as the time interval of MST minus MPFS. The relationship between MPFS and MST was modeled in a linear function. We used the coefficient of determination (r(2)) to assess the correlation between them. Seventy trials with 145 chemotherapy arms were identified. Overall, median SPP was 4.7 months, and a steady improvement in SPP was observed over the 20 years (9.414-day increase per year; p<0.001) in parallel to the increase in MST (11.253-day increase per year; p<0.001); MPFS improved little (1.863-day increase per year). Overall, a stronger association was observed between MST and SPP (r(2) = 0.8917) than MST and MPFS time (r(2) = 0.2563), suggesting SPP and MPFS could account for 89% and 25% of the variation in MST, respectively. The association between MST and SPP became closer over the years (r(2) = 0.4428, 0.7242, and 0.9081 in 1988-1994, 1995-2001, and 2002-2007, respectively). CONCLUSIONS: SPP has become more closely associated with OS, potentially because of intensive post-study treatments. Even in advanced NSCLC, a PFS advantage is unlikely to be associated with an OS advantage any longer due to this increasing impact of SPP on OS, and that the prolongation of SPP might limit the original role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Humanos , Tasa de Supervivencia , Resultado del Tratamiento

RESUMEN

A 51-year-old female presented with left facial palsy. She had adenocarcinoma of the lung with multiple brain metastases. The primary tumor regressed after treatment with gefitinib, however, neurological symptoms progressed rapidly because of meningeal carcinomatosis, when a deletion mutation in exon 19 of the epidermal growth factor receptor in cells from her cerebrospinal fluid was detected. After performing lumbo-peritoneal shunting, her symptoms improved dramatically and she had been well without peritoneal dissemination for 15 months, continuing gefitinib treatment. Finally, she died 18 months after lumbo-peritoneal shunting. A T790M acquired-resistance mutation in exon 20 of the epidermal growth factor receptor was found from her mesenteric lymph nodes and cerebrospinal fluid at autopsy. A lumbo-peritoneal shunt might be considered for meningeal carcinomatosis refractory to gefitinib treatment without an emergence of a T790M mutation.

Asunto(s)

Antineoplásicos/uso terapéutico , Derivaciones del Líquido Cefalorraquídeo , Neoplasias Meníngeas/terapia , Quinazolinas/uso terapéutico , Femenino , Gefitinib , Humanos , Neoplasias Meníngeas/tratamiento farmacológico , Persona de Mediana Edad

RESUMEN

A 68-year-old man with emphysema was admitted with cough and bloody sputum. Chest radiography revealed infiltrative shadows in the right upper lung. Microbiologically, an acid-fast bacillus was detected in the culture of sputum (Gaffky (+)), but both tuberculosis bacillus (TB) and Mycobacterium avium complex (MAC) were negative by the PCR method. Combination chemotherapy, which included isoniazid, rifampicin, ethambutol and pyradinamide, was initiated under a tentative diagnosis of TB. His clinical symptoms and radiographic findings improved. After 4 months, the strain of acid-fast bacilli was identified as Mycobacterium xenopi by DNA-DNA hybridization (DDH) method. However, analysis of base sequences from sputum samples using 16S rDNA confirmed the identity of all tested isolates as Mycobacterium heckeshornense. M. heckeshornense could not be identified by the DDH method in Japan. When M. xenopi is detected, it is essential to perform both sequencing of 16S rDNA and a biochemical method for the purpose of distinguishing M. heckeshornense from M. xenopi.

Asunto(s)

Infecciones por Mycoplasma/microbiología , Mycoplasma/aislamiento & purificación , Anciano , Sondas de ADN , Humanos , Masculino

RESUMEN

The risks of secondary lung cancer in patients with early stage non-small and small cell lung cancers are estimated to be 1-2% and 2-10% per patient per year, respectively. Surprisingly, the incidence of second primary cancer in locally advanced non-small cell lung cancer at 10 years, following cisplatin-based chemotherapy with concurrent radiotherapy, increases to 61%. Those patients, on the road to being cured, cannot overlook the possibility of developing a second primary cancer. We developed a second primary lung cancer model using cisplatin as a carcinogen in A/J mice to screen for chemopreventive agents for a second malignancy. In the primary lung tumour model, 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), benzo(a)pyrene (BaP), urethane induces specific K-ras mutations in codon 12, codon 12, and codon 61, respectively, in the A/J mice. In this study, we investigated the mechanisms of carcinogenicity by cisplatin in the A/J mice. In the cisplatin-induced tumours, we found no K-ras codon 12 mutation, which is the major mutation induced by NNK or BaP. K-ras gene mutations in codon 13 and codon 61 were found in one tumour (4%) and five tumours (17.8%), respectively. These findings suggest that cisplatin is partially related to K-ras codon 61 mutations, and that the mechanism of carcinogenicity by cisplatin is different from that by NNK or BaP.

Asunto(s)

Carcinógenos/toxicidad , Cisplatino/toxicidad , Genes ras , Neoplasias Pulmonares/genética , Neoplasias Primarias Secundarias/genética , Mutación Puntual , Adenocarcinoma/inducido químicamente , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/prevención & control , Animales , Benzo(a)pireno/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/inducido químicamente , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Cisplatino/efectos adversos , Codón , Femenino , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/prevención & control , Ratones , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/prevención & control , Nitrosaminas/toxicidad

RESUMEN

Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18-21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient.

Asunto(s)

Adenocarcinoma/genética , Adenomatosis Pulmonar/genética , Receptores ErbB/genética , Genes erbB-1 , Neoplasias Pulmonares/genética , Mutación , Neoplasias Primarias Múltiples/genética , Adenocarcinoma/tratamiento farmacológico , Adenomatosis Pulmonar/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Exones , Femenino , Gefitinib , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Neoplasias Primarias Múltiples/tratamiento farmacológico , Quinazolinas/uso terapéutico , Estudios Retrospectivos

RESUMEN

Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxy-campthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN-38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15+/-1.6 and 12+/-2.8 microM of gefitinib, respectively; 15+/-0.51 and 14+/-3.9 microM of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 microM gefitinib or 8 microM imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/biosíntesis , Benzamidas , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Carcinoma de Células Pequeñas/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Gefitinib , Humanos , Mesilato de Imatinib , Irinotecán , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Quinazolinas/administración & dosificación

RESUMEN

Despite its tremendous antitumor effect in a subset of patients with non-small cell lung cancer (NSCLC), the exact mechanism of gefitinib-induced cell death has not been fully determined. In this study, forms of cell death in various NSCLC cell lines after gefitinib exposure was analyzed to elucidate the cell death mechanism of gefitinib. Though higher concentration of gefitinib (10 microM) induced extensive apoptosis in two cell lines (EGFR-mutated PC-9 cells and EGFR wild- type EBC-2/R cells), clinically relevant concentrations of gefitinib (1 microM) induced prominent premature senescence instead of apoptosis in these cells. This induction of senescence was preceded by immediate increase of p16INK4A, p21WAF1/Cip1 and p27Kip1 levels and subsequent G1 cell cycle arrest. These phenomena were not observed in gefitinib-resistant (RERF-LC-MS) cells. Additionally, ex vivo exposure to gefitinib induced senescence in short-term cultured tumor cells that were obtained from malignant pleural effusion of a patient with NSCLC, whose tumor was later revealed to be clinically sensitive to gefitinib. Our results indicate that senescence might be a major anti-tumor mechanism of gefitinib in these NSCLC cells regardless of the EGFR gene mutation status.

Asunto(s)

Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Senescencia Celular , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Quinazolinas/farmacología , Apoptosis , Muerte Celular , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Análisis Mutacional de ADN , Gefitinib , Humanos

RESUMEN

A 56-year-old woman was admitted to our hospital for treatment of non-specific interstitial pneumonitis (NSIP). The patient started prednisone treatment, but one month later treatment with voglibose, an alpha-glucosidase inhibitor (alpha-GI), was started because of prednisone-induced diabetes mellitus. One week later, a massive volume of free air below the diaphragm was detected by a chest X-ray examination. An abdominal CT examination demonstrated pneumatosis coli and the patient was diagnosed with pneumatosis cystoides intestinalis (PCI). Voglibose was discontinued and parenteral nutrition and oxygen inhalation were initiated. Radiographic findings of PCI disappeared within 7 days. We encountered a rare case of PCI, that was associated with alpha-GI treatment.

Asunto(s)

Diabetes Mellitus/inducido químicamente , Hipoglucemiantes/efectos adversos , Inositol/análogos & derivados , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Neumatosis Cistoide Intestinal/etiología , Diabetes Mellitus/tratamiento farmacológico , Inhibidores Enzimáticos/efectos adversos , Femenino , Glucocorticoides/efectos adversos , Glucosidasas/antagonistas & inhibidores , Humanos , Inositol/efectos adversos , Persona de Mediana Edad , Neumatosis Cistoide Intestinal/diagnóstico , Neumatosis Cistoide Intestinal/patología , Prednisona/efectos adversos

RESUMEN

BACKGROUND: Gefitinib ('Iressa', ZD1839), an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), has shown antitumor activity in refractory patients with non-small-cell lung cancer (NSCLC) in clinical trials. We have retrospectively analyzed the efficacy and tolerability of gefitinib in patients with advanced NSCLC treated at Okayama University Hospital. METHODS: We reviewed the clinical records of 57 patients with advanced NSCLC who had received 250 mg/day gefitinib at our hospital between November 2000 and May 2003. Correlations between the sensitivity of brain metastases and extracranial disease following treatment with gefitinib were also investigated. RESULTS: Extracranial objective responses were observed in 15 (27%; 95% confidence interval 15.8-40.3%) patients. Fourteen out of 57 patients had brain metastases; six experienced objective responses (one complete response, CR and five partial responses, PR) and eight had stable disease (SD) in the brain. Seven out of 14 patients with brain metastases experienced objective responses in their extracranial tumors and, interestingly, objective responses in the brain were observed in six (86%) of these patients. Multivariate analysis found that advanced age (> or = 70 years) and the presence of brain metastases were associated with clinical response to gefitinib (P = 0.01 and 0.05, respectively), and that female patients were more likely to respond. Median survival and median duration of response were 9.1 and 7.7 months, respectively. The majority of adverse events (AEs) were mild and reversible skin and gastrointestinal disorders, with grade 3 adverse events observed in six (11%) patients. CONCLUSIONS: This retrospective analysis has found that gefitinib is effective and well tolerated in patients with refractory NSCLC, confirming previous phase II trial data. Interestingly, gefitinib appeared to be effective for brain metastases as well as extracranial tumors. Further prospective trials are warranted to evaluate the efficacy of gefitinib in elderly patients and in patients with brain metastases.

Asunto(s)

Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/patología , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Femenino , Gefitinib , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/efectos adversos , Estudios Retrospectivos , Factores Sexuales

RESUMEN

PURPOSE: To determine the maximum-tolerated dose (MTD) of irinotecan and paclitaxel in this two-drug combination, and to investigate a sequence-dependent effect in the pharmacokinetics of these drugs, we conducted a phase I study in chemo-naïve patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled in this study. Both irinotecan and paclitaxel were administered on days 1 and 8, and repeated every 3 weeks. The starting dose of both drugs was 40 mg/m2 which was then alternately increased by 10 mg/m2 increments. In the first cycle, irinotecan was initially administered and followed by paclitaxel infusion, while the sequence of drug administration was reversed in the second cycle. Blood samples for pharmacokinetic analysis were obtained on day 1 of the first and second cycles. RESULTS: Nine patients received a total of 12 cycles, which were evaluated for toxicity and efficacy. The main hematological toxicity was neutropenia. Grades 3 or more neutropenia was observed in 67% of cycles at dose level 2. The main non-hematological toxicities were grade 3 febrile neutropenia, supraventricular arrhythmia, and grade 2 hepatic dysfunction. The MTD of irinotecan and paclitaxel were 40 and 50 mg/m2, respectively. In the pharmacokinetic analysis, the maximum concentration of paclitaxel was elevated in a dose-dependent manner. There was a trend toward elevation of the area under the plasma concentration-time curve (AUC) of irinotecan and a decline of the AUC of paclitaxel in cycle 1 (irinotecan followed by paclitaxel), compared with those in cycle 2 (paclitaxel followed by irinotecan). Hepatic toxicity was strongly associated with the AUC of irinotecan (r = 0.894, P < 0.0001). The objective response was not observed in the nine patients. CONCLUSION: The combination of irinotecan and paclitaxel with this schedule produced considerable toxicities without any antitumor effect for advanced NSCLC. The different schedule of administration or other combinations should be investigated.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Infusiones Intravenosas , Irinotecán , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética

RESUMEN

Primary effusion lymphoma (PEL) is a newly described high-grade B cell lymphoma developing in association with human herpes virus type 8 (HHV-8) in human immunodeficiency virus (HIV)-infecting individuals. Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by reduced serum immunoglobulin and heterogeneous clinical features. The risk of cancer in CVID patients is increased. Here, we describe a PEL that developed in the pleural and pericardial cavities of an HIV-negative and HHV-8-negative patient with CVID.

Asunto(s)

Inmunodeficiencia Variable Común/diagnóstico , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8 , Linfoma/etiología , Derrame Pleural Maligno/etiología , Neoplasias Pleurales/etiología , Femenino , Seronegatividad para VIH , Humanos , Japón , Linfoma/patología , Persona de Mediana Edad , Derrame Pleural Maligno/patología , Neoplasias Pleurales/patología