RESUMO
BACKGROUND: This study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. RESULTS: The combination of carboplatin at an area under the concentration-time curve (AUC) of 5, and 500 mg/m(2) pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68-216 days) and the median overall survival time was 461 days (95% CI 168-754 days). CONCLUSIONS: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m(2)) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.
Assuntos
Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutamatos/administração & dosagem , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Estadiamento de Neoplasias , Pemetrexede , Taxa de SobrevidaRESUMO
OBJECTIVES: No objective method to measure skin involvement in SSc has been established. We developed a novel method using a computer-linked device to simultaneously quantify physical properties of the skin such as hardness, elasticity and viscosity. METHODS: Skin hardness was calculated by measuring the depth of an indenter pressed onto the skin. The Voigt model was used to calculate skin elasticity, viscosity, visco-elastic ratio and relaxation time by analysing the waveform of skin surface behaviour. The results were compared with the modified Rodnan skin score (mRSS) obtained at 17 sites on the bodies of 20 SSc patients and 20 healthy controls. A functional assessment questionnaire was administered to determine how skin hardness represents a patient's disability. We also examined intra- and inter-observer variability to determine the reliability of this method. RESULTS: The crude hardness obtained with this device correlated well with the standard hardness specified by the American Society for Testing and Materials (ASTM, r = 0.957). A close relationship between hardness and total mRSS was also observed (r = 0.832). Skin elasticity correlated positively, and relaxation time negatively with mRSS. Functional disability correlated more closely with skin hardness (r = 0.643) than with mRSS (r = 0.517). Intra- and inter-observer variabilities were 7.63 and 19.76%, respectively, which were lower than those reported for mRSS. CONCLUSIONS: Increases in hardness and elasticity as well as shortening of relaxation time constitute objective characteristics of skin involvement in SSc. The system devised by us proved to be able to assess skin abnormalities of SSc with high reliability.
Assuntos
Escleroderma Sistêmico/fisiopatologia , Pele/fisiopatologia , Adulto , Idoso , Elasticidade , Feminino , Dureza , Testes de Dureza/instrumentação , Testes de Dureza/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Índice de Gravidade de Doença , Processamento de Sinais Assistido por Computador , ViscosidadeRESUMO
The operative repair of Ebstein's anomaly is performed usually during the younger age. On the other hand, the operative indication of asymptomatic Ebstein's anomaly in adult patients has not been clearly defined. We encountered a 71-year-old female patient with asymptomatic Ebstein's anomaly. Because of severe tricuspid regurgitation (TR) and right ventricular dilatation, we repaired the tricuspid valve configuration. The operation was successful and medium term result was excellent. We believe that severe TR with moderate right ventricular dysfunction can be the operative indication in adult patients with asymptomatic Ebstein's anomaly especially when tricuspid valve repair is possible.
Assuntos
Anomalia de Ebstein/cirurgia , Insuficiência da Valva Tricúspide/cirurgia , Valva Tricúspide/cirurgia , Idoso , Procedimentos Cirúrgicos Cardíacos , Diagnóstico por Imagem , Anomalia de Ebstein/complicações , Anomalia de Ebstein/diagnóstico , Feminino , Humanos , Resultado do Tratamento , Insuficiência da Valva Tricúspide/etiologiaRESUMO
Wild-type Wilms' tumor gene WT1 is highly expressed not only in hematopoietic malignancies, including leukemia and myelodysplastic syndromes (MDS), but also in various kinds of solid tumors. Human cytotoxic T lymphocytes (CTLs) which could specifically lyse WT1-expressing tumor cells with HLA class I restriction were generated in vitro. We have also demonstrated that mice immunized with the WT1 peptide or WT1 cDNA rejected challenges by WT1-expressing tumor cells and survived with no signs of auto-aggression to normal organs which physiologically expressed WT1 in prophylactic and therapeutic models. Furthermore, we and others detected IgM and IgG WT1 antibodies in the patients with hematopoietic malignancies, indicating that WT1 protein was highly immunogenic, and that immunoglobulin class-switch-inducing WT1-specific cellular immune responses were elicited in the patients. CD8+ WT1-specific CTLs were also detected in peripheral blood or tumor-draining lymph nodes of cancer patients. These results provided us with the rationale for elicitation of CTL responses targeting the WT1 product for cancer immunotherapy. On the basis of the findings mentioned above, we performed a phase I clinical trial of WT1 peptide cancer vaccine for the patients with malignant neoplasms. These results strongly suggested that WT1 peptide cancer vaccine had efficacy in the clinical setting, because clinical responses, including reduction of leukemic blast cells or regression of tumor masses, were observed after the WT1 vaccination in patients with hematopoietic malignancies or solid cancers. The power of TAA-derived cancer vaccine may be enhanced by combination with stronger adjuvants, helper peptide, or conventional treatments such as molecular-target-based drugs.
Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas WT1/imunologia , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Desenho de Fármacos , Genes do Tumor de Wilms , Neoplasias Hematológicas/terapia , Humanos , Camundongos , PeptídeosRESUMO
The Wilms' tumor gene WT1 is highly expressed in leukemias and myelodysplastic syndrome (MDS), and WT1 expression levels increase along with the disease progression in chronic myeloid leukemia and MDS. We previously reported that IgM and IgG WT1 antibodies were detected with significantly higher detection rate and antibody titers in leukemias and MDS compared to those in healthy volunteers. In this study, whether IgG humoral immune responses against WT1 protein were Th1- or Th2-type were determined by measurement of four subclasses of IgG WT1 antibody, IgG1, IgG2, IgG3, and IgG4. In leukemias and MDS, Th1-type WT1 antibodies such as IgG1, IgG2, and IgG3 were significantly increased in both detection rate and antibody titers compared to those in healthy volunteers, whereas Th2-type WT1 antibody such as IgG4 did not increase. These results showed that Th1-biased humoral immune responses against WT1 protein were generated in leukemias and MDS. These results should allow us to consider that Th1-biased cellular immune responses against WT1 protein, which was essentially needed for cancer immunotherapy targeting WT1, should be elicited in patients with hematopoietic malignancies.
Assuntos
Formação de Anticorpos , Neoplasias Hematológicas/imunologia , Síndromes Mielodisplásicas/genética , Células Th1/imunologia , Proteínas WT1/genética , Proteínas WT1/imunologia , Neoplasias Hematológicas/genética , Humanos , Imunoglobulina G/sangue , Leucemia/genética , Leucemia/imunologia , Linfócitos/imunologia , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Valores de ReferênciaRESUMO
Four monoclonal antibodies to MH134 murine syngeneic hepatoma cells, 3H1, 7C2, 11G2, and 12A2, were produced by hybridomas constructed by fusing P3-X63-Ag8-U1 murine myeloma cells with spleen cells of a C3H/HeN mouse immunized with the syngeneic tumor cells. Immunodiffusion analysis with rabbit anti-mouse immunoglobulin antisera showed that 3H1, 7C2, 11G2, and 12A2 are IgG2a, IgM, IgG1, and IgG2a, respectively. Enzyme-linked immunosorbent assay using cells of five syngeneic tumor lines, MH134, MM102, MM46, MM48, and X5563, and lymph node cells of C3H/HeN and C57BL/6 mice showed that 3H1 specifically bound to MH134 tumor cells, whereas 7C2, 11G2, and 12A2 reacted not only with MH134 but also with MM102 and MM46 tumor cells. None of these monoclonal antibodies bound either to cells of MM48 or X5563 tumor lines or to normal lymph node cells. These results strongly suggest that MH134 tumor cells display at least two kinds of tumor-associated antigens on their cell surfaces: one is expressed uniquely by MH134 tumor cells, which are recognized by 3H1; the other is commonly shared by MH134, MM102, and MM46 tumor cells, which are determined by the other three antibodies. 3H1, 11G2, and 12A2 but not 7C2 were found to be able to induce antibody-dependent cellular cytotoxicity (ADCC) against MH134 tumor cells. Target specificity of ADCC induced by these monoclonal antibodies was identical with that seen in enzyme-linked immunosorbent assay. 3H1, 7C2, and 12A2 but not 11G2 exhibited complement-dependent cytotoxicity, showing the same specificity in target cell lysis as that seen in enzyme-linked immunosorbent assay or ADCC. Pretreatment of MH134 tumor cells with 7C2 inhibited ADCC of both 11G2 and 12A2. Pretreatment of the tumor cells with 11G2 inhibited complement-dependent cytotoxicity of both 7C2 and 12A2. Neither ADCC nor complement-dependent cytotoxicity of 3H1 was inhibited by the pretreatment of the cells with 7C2 or 11G2. These results strongly suggest that tumor-associated antigens recognized by 3H1 are located apart from that recognized by 7C2, 11G2, and 12A2 and that the binding sites of the latter three antibodies are closely associated with, or identical with, each other in the tumor-associated antigen. The ability of 12A2 to induce ADCC against MH134 tumor cells was significantly stronger than that of 3H1 or 11G2.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Anticorpos Monoclonais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Animais , Proteínas do Sistema Complemento/imunologia , Ensaio de Imunoadsorção Enzimática , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/terapiaRESUMO
The in vivo antitumor effect of i.p. injection of allogeneic spleen cells was investigated. ACl rats were inoculated i.p. with 10(4) AMC-60 syngeneic fibrosarcoma cells and given injections i.p. of 4 X 10(7) Wistar spleen cells once a week for 3 wk from 1 day after tumor inoculation. This treatment significantly prolonged the survival period of the tumor-bearing rats. A similar effect was obtained by i.p. injections of Lewis spleen cells. Injection i.p. into ACl rats of spleen cells of these rat strains resulted in the apparent augmentation of cytolytic activity of peritoneal adherent but not of nonadherent cells against AMC-60 tumor cells. The cytotoxicity was exhibited nonspecifically to cells of a variety of tumor lines but not to concanavalin A blasts of ACl spleen cells and was inhibited by the addition of carrageenan. Irradiation (2000 R) of Lewis spleen cells or fractionation of the allogeneic spleen cells using nylon wool columns revealed that a radiosensitive and nylon wool-passed cell population, presumably a T-cell population, of the allogeneic spleen cells is responsible for the augmentation of peritoneal macrophage tumoricidal activity in ACl rats. Further, Lewis spleen cells irradiated at 2000 R neither augmented peritoneal macrophage cytotoxicity nor prolonged the survival period of ACl rats bearing AMC-60 tumor, suggesting that the augmentation of peritoneal macrophage cytotoxicity plays a major role in the in vivo antitumor effect of the allogeneic spleen cell transfer. ACl rats were given injections i.p. of 4 X 10(7) Lewis spleen cells. Two days after injection, cells including peritoneal cells of the ACl rats and Lewis spleen cells remaining in the peritoneal cavities were obtained by peritoneal lavages and then incubated for 5 days. Significant blastogenic proliferation was observed, and the supernatant of the culture was shown to be able to render thioglycollate-induced peritoneal macrophages of ACl rats cytotoxic to AMC-60 tumor cells, indicating that a certain cell population of the cell mixture produced a lymphokine(s) resembling macrophage activating factor (MAF) during the incubation. When ACl rats were given injections i.p. of irradiated Lewis spleen cells, neither the blastogenic proliferation nor the generation of MAF activity in the culture supernatant was observed. Indirect immunofluorescence analysis using rabbit anti-ACl and anti-Lewis antisera revealed that as many irradiated Lewis spleen cells were remaining in the peritoneal cavities as normal Lewis spleen cells 2 days after injection into ACl rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Macrófagos/imunologia , Sarcoma Experimental/terapia , Baço/imunologia , Animais , Células Cultivadas , Citotoxicidade Imunológica , Fibrossarcoma/terapia , Imunoterapia , Linfocinas/biossíntese , Ativação de Macrófagos , Fatores Ativadores de Macrófagos , Masculino , Ratos , Ratos Endogâmicos , Sarcoma Experimental/imunologiaRESUMO
Cell-mediated cytotoxicity against syngeneic MC104 fibrosarcoma cells was detected in C57BL/6N mice 7 days after tumor inoculation in the hind foot. This cytotoxicity was undetectable by Day 14 in the Winn test using spleen and draining popliteal lymph node (DPLN) cells. Similar results were obtained with the 51Cr release assay following in vitro activation of these lymphoid cells with mitomycin C-treated tumor cells. The antitumor cytotoxicity was shown to be mediated by T-cells. Spleen but not DPLN cells from 14-day tumor bearers enhanced tumor growth in the Winn test, suggesting the presence of immunosuppressor cells in the spleen. Two intralesional injections of 50 microgram of cell wall skeleton (CWS) of Nocardia rubra on Days 2 and 7 resulted in apparent tumor growth inhibition and prolongation of the survival period of tumor bearers. DPLN cells from tumor bearers treated with N. rubra CWS exhibited significant recovery in the cytotoxicity tested on Day 14, whereas the recovery in that of spleen cells was not apparent. The cytotoxicity augmented by N. rubra CWS was specific to MC104 tumor cells and was shown to be mediated by T-cells. These cytotoxic T-cells were shown to be able to localize not only in DPLN but also in the spleen and tumor in mice receiving the intralesional immunotherapy with N. rubra CWS. These results suggest that T-cell-mediated cytotoxicity against syngeneic tumor can be augmented by N. rubra CWS and might play an important role in the systemic development of its antitumor effect, although the effector cell increase in the spleen might be suppressed by splenic suppressor cells during tumor growth.
Assuntos
Citotoxicidade Imunológica , Nocardia/imunologia , Sarcoma Experimental/imunologia , Linfócitos T/imunologia , Animais , Parede Celular/imunologia , Fibrossarcoma/imunologia , Imunoterapia , Linfonodos/imunologia , Camundongos , Sarcoma Experimental/terapia , Baço/imunologiaRESUMO
Primary growth of AMC 60 fibrosarcoma inoculated into the hind leg of ACI/N rats resulted in occasional generation of concomitant resistance to growth of a second graft of the same tumor cells in the peritoneal or pleural cavity. Using this syngeneic tumor-host system, experiments were carried out to elucidate the effect of intratumoral injections of an immunomodulator, Nocardia rubra cell wall skeleton (N-CWS), on concomitant immunity. Rats bearing a solid tumor into which N-CWS was repeatedly injected showed a significant inhibitory effect on the proliferation of the tumor cells inoculated secondarily into the peritoneal cavity, i.e., concomitant immunity, as compared to control groups of normal, N-CWS-treated and solid tumor-bearing rats. Peritoneal macrophages, when harvested after i.p. tumor inoculation into the N-CWS treated solid tumor-bearing rats, were found to be significantly potentiated for tumoricidal activity against [5-125I]iodo-2'-deoxyuridine-labeled AMC tumor cells. These potentiated macrophages were induced tumor specifically by i.p. inoculation of AMC tumor cells but not by unrelated syngeneic reticulosarcoma SL 1 tumor cells; nevertheless their tumoricidal activity was observed tumor nonspecifically for the SL 1 tumor cells. Additional experiments revealed that nonadherent peritoneal cells were only weakly tumoricidal and that the macrophage tumoricidal activity was completely abolished in the presence of carrageenan. Thus in the model presented here, it is possible to conclude that the augmentation of concomitant immunity by injection of N-CWS into a primary solid tumor is mainly due to potentiation of the tumoricidal activity of tumor-associated macrophages in the peritoneal cavity. Although the underlying mechanism by which concomitant resistance can be augmented by intratumoral injection of N-CWS remains undetermined, the existence of a tumor-specific trigger for induction of potentiated tumoricidal macrophages may indicate that N-CWS when injected repeatedly into the tumor tissue plays an important role in augmenting a pre-existing, weak, tumor-specific cell-mediated immune response leading to activation of macrophages.
Assuntos
Nocardia/imunologia , Sarcoma Experimental/terapia , Animais , Carragenina/uso terapêutico , Parede Celular/imunologia , Imunoterapia , Macrófagos/imunologia , Masculino , Camundongos , Transplante de Neoplasias , Cavidade Peritoneal/imunologiaRESUMO
A carcinoembryonic antigen (CEA)-producing human lung cancer cell line (A549), a nonproducing human lung cancer cell line (CADO-LC9), and a human uterine cervical cancer (HeLa) were transfected with the herpes simplex virus thymidine kinase (HSV-TK) gene regulated by 445 nucleotides upstream from the translational start of CEA gene. Fifty % growth inhibitory concentration of ganciclovir (GCV) was 0.57 micron for HSV-TK-transfected A549; relative sensitivity to GCV was more than 1000 times higher compared to the 50% growth inhibitory concentration of the parental cell line. Both CADO-LC9 and HeLa transfected with HSV-TK were still resistant to GCV. There was no difference in either morphology or doubling time between HSV-TK-transfected and parental clones. Injections (i.p.) of GCV resulted in significant regression of HSV-TK-transfected A549 tumors in nude mice. These data show the possibility of gene therapy using the cell type-specific promoter of CEA gene against CEA-producing adenocarcinoma of the lung.
Assuntos
Adenocarcinoma/terapia , Biomarcadores Tumorais/metabolismo , Antígeno Carcinoembrionário/metabolismo , Carcinoma de Células Pequenas/terapia , Ganciclovir/farmacologia , Genes Virais , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Simplexvirus/genética , Timidina Quinase/genética , Adenocarcinoma/metabolismo , Sequência de Bases , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/genética , Carcinoma de Células Pequenas/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Células HeLa/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Dados de Sequência Molecular , Recidiva Local de Neoplasia/terapia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Simplexvirus/enzimologia , Transfecção , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/terapiaRESUMO
The ability of lymphokine-activated killer (LAK) cells to mediate antibody-dependent cellular cytotoxicity and its efficacy against a LAK-resistant tumor were investigated. Cells of the MH134 murine hepatoma line are scarcely lysed by LAK cells generated in vitro by incubation of C3H/HeN mouse spleen cells with human recombinant interleukin 2 (rIL 2). However, the splenic LAK cells potently lysed the LAK-resistant tumor cells in the presence of 11G2, a monoclonal antibody (MAb) of the IgG1 isotype reactive with a part of MM antigen. Peritoneal cells induced by daily i.p. injections of rIL 2 not only exhibited LAK activity but also mediated antibody-dependent cellular cytotoxicity against MH134 tumor cells in the presence of 11G2. The peritoneal cells exhibiting these cytotoxic activities were found to be nonadherent and nonphagocytic mononuclear cells possessing a similar cell surface phenotype as that of splenic LAK cells, that is Thy-1.2+ approximately -, Lyt-1.1-, Lyt-2.1-, and asialo GM1+. Treatment of spleen cells with antibodies and complement before culture with rIL 2 revealed that the phenotype of splenic LAK precursors is Thy-1.2- and asialo GM1+. The in vivo induction of peritoneal LAK cells in response to i.p. injections of rIL 2 was markedly depressed in C57BL/6 beige mice but was normally accomplished in BALB/c nude mice. Combined therapy of C3H/HeN mice bearing MH134 ascitic tumor with i.p. injection of rIL 2 and 11G2 brought about potent suppression of the tumor growth, resulting in the significant increase in the number of tumor-free mice, whereas neither rIL 2 nor the MAb could exhibit such a potent antitumor effect when used alone. Injection (i.v.) of anti-asialo GM1 antibody not only blocked the induction of peritoneal LAK cells by rIL 2 but also abrogated the development of the antitumor effect of the combined therapy. These results strongly suggest that combination of antitumor MAbs capable of inducing antibody-dependent cellular cytotoxicity with rIL 2 therapy could result in the generation of potent antitumor effects against LAK-resistant tumors and that asialo GM1-positive non-T-cell populations including cells of the natural killer cell lineage are essential, at least in part, for development of the antitumor effects of the combined therapy with rIL 2 and MAbs.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Gangliosídeo G(M1) , Interleucina-2/uso terapêutico , Células Matadoras Naturais/imunologia , Linfocinas/farmacologia , Neoplasias Experimentais/terapia , Animais , Terapia Combinada , Glicoesfingolipídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Fenótipo , Proteínas Recombinantes/uso terapêuticoRESUMO
We have examined the deletion of the long arm of chromosome 5 (5q) in 59 cases of advanced lung cancer [39 cases of small cell lung cancer (SCLC), 20 cases of non-SCLC] using 12 restriction fragment length polymorphism markers on 5q. Of 59 lung cancer cases, 48 (81%) exhibited deletion at any portion of the 5q locus (loci). Such a high frequency of 5q deletion has not been reported in surgically resectable non-SCLC. One SCLC case showed a 5q deletion only in metastatic sites but not in the primary cancer. These data suggest that the inactivation of putative tumor-suppressor gene(s) on 5q may be a late event in the progression of lung cancer. There was no significant difference in frequency of 5q deletion between SCLC and non-SCLC. Compared to non-SCLC, however, SCLC usually showed widespread deletion on 5q. While the most frequent target region was estimated to be about 3-5 megabases at 5q21 around the adenomatous polyposis coli (APC) gene locus, some cases showed more telomeric deletion (5q33-35), suggesting that there are at least two different tumor-suppressor genes on 5q associated with the progression of lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Pequenas/genética , Deleção Cromossômica , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/patologia , Mapeamento Cromossômico , DNA de Neoplasias/análise , Eletroforese em Gel de Ágar , Genes APC , Genes Supressores de Tumor , Marcadores Genéticos , Neoplasias Pulmonares/patologia , Polimorfismo de Fragmento de RestriçãoRESUMO
PURPOSE: To determine the response rate, survival, and toxicity of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, in refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed SCLC were entered onto the trial. All 25 patients had been pretreated with some form of cisplatin-based combination chemotherapy and had also received previous etoposide- or anthracyclinecontaining chemotherapy. The median time off chemotherapy was 6.7 months (range, 0.9 to 23.5). Patients were treated at 4-week intervals using CPT-11 (a starting dose of 70 mg/m2 intravenously on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3), with a subsequent dose based on toxicity. In addition, recombinant human granulocyte colony-stimulating factor (rhG-CSF; 2 microg/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. RESULTS: All patients were assessable for toxicity and survival. Twenty-four patients were assessable for response. There were 14 partial responses (PRs) and three complete responses (CRs), for an overall response rate of 71% (95% confidence interval, 53% to 89%). The median response duration was 4.6 months. Median survival was 271 days. Major toxicities were myelosuppression (predominantly leukopenia) and diarrhea. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 56% and 20% of patients, respectively. Grade 3 to 4 diarrhea was observed in 4%. There was one treatment-related death due to severe myelosuppression. CONCLUSION: A combination of CPT-11 and etoposide with rhG-CSF support is an active therapy against refractory or relapsed SCLC and deserves to be studied more extensively in a phase III trial.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Leukemia-specific promoters and enhancers for gene therapy had never been reported. Since the Wilms' tumor gene WT1 is overexpressed in almost all types of leukemia, WT1 is an ideal target of leukemia-specific therapy. To explore the possibility of gene therapy for leukemia using WT1 promoter and enhancer, their activities in several kinds of cells were analyzed by using the enhanced green fluorescent protein (EGFP) gene as a reporter. First, we identified the best combination (654P/EGFP/int3- enh/3'-enh vector) of the 654-bp WT1 promoter and the two WT1 enhancers located in intron 3 and at the 3' end of the WT1 gene for inducing EGFP expression in K562 cells, which endogenously expressed WT1. When this was transfected into WT1-expressing leukemia cells (K562, HEL), WT1-nonexpressing hematopoietic cells (Daudi, U937), and WT1-expressing nonhematopoietic cells (TYK-nu-CPr, SW480, 293 T), 19.8, 22.9, 1.47, 1.43, 4.50, 4.16, and 1.09 times EGFP expression was induced, respectively, compared to that by the promoter-less EGFP vector. These results showed that the 654P/EGFP/int3-enh/3'-enh vector specifically induced high levels of EGFP expression in WT1-expressing leukemia cells. 654P/int3- enh/3'-enh vector containing transgenes such as suicide genes might become useful tools for leukemia-specific gene therapy.
Assuntos
Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Neoplasias/genética , Transgenes/fisiologia , Proteínas WT1/genética , Vetores Genéticos/genética , Proteínas de Fluorescência Verde , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Neoplasias/metabolismo , Neoplasias/terapia , Transdução Genética , Células Tumorais Cultivadas , Proteínas WT1/metabolismoRESUMO
Primitive hematopoietic progenitor cells such as severe combined immunodeficiency- repopulating cells and long-term culture-initiating cells are enriched in CD34+CD38- cells derived from various stem cell sources. In this study, to elucidate the features of such primitive cells at the molecular level, we tried to isolate genes that were preferentially expressed in umbilical cord blood (CB)-derived CD34+CD38- cells by subtractive hybridization. The gene for VPAC1 receptor, a receptor for the neuropeptide vasoactive intestinal peptide (VIP), was thereby isolated and it was shown that this gene was expressed in both CD34+CD38- and CD34+CD38+ CB cells and that the expression levels were higher in CD34+CD38- CB cells. Next, we assessed the effects of VIP on the proliferation of CD34+ CB cells using in vitro culture systems. In serum-free single-cell suspension culture, VIP enhanced clonal growth of CD34+ CB cells in synergy with FLT3 ligand (FL), stem cell factor (SCF), and thrombopoietin (TPO). In serum-free clonogenic assays, VIP promoted myeloid (colony-forming unit-granulocyte/macrophage (CFU-GM)) and mixed (CFU-Mix) colony formations. Furthermore, in Dexter-type long-term cultures, VIP increased colony-forming cells at week 5 of culture. These results suggest that VIP functions as a growth-promoting factor of CB-derived hematopoetic progenitor cells.
Assuntos
ADP-Ribosil Ciclase/análise , Antígenos CD34/análise , Antígenos CD/análise , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Receptores de Peptídeo Intestinal Vasoativo/análise , Peptídeo Intestinal Vasoativo/farmacologia , ADP-Ribosil Ciclase 1 , Southern Blotting , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Células-Tronco Hematopoéticas/química , Células-Tronco Hematopoéticas/fisiologia , Humanos , Glicoproteínas de Membrana , Receptores Tipo I de Polipeptídeo Intestinal VasoativoRESUMO
Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown. To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC. p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma. On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/mortalidade , Ciclinas/análise , Neoplasias Pulmonares/mortalidade , Proteínas de Neoplasias/análise , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Adulto , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Adenoescamoso/química , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/mortalidade , Carcinoma Adenoescamoso/terapia , Carcinoma de Células Grandes/química , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/mortalidade , Carcinoma de Células Grandes/terapia , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Ciclo Celular , Quimioterapia Adjuvante , Terapia Combinada , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Ciclinas/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Tábuas de Vida , Neoplasias Pulmonares/química , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Pneumonectomia , Prognóstico , Análise de SobrevidaAssuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Doenças do Colo/tratamento farmacológico , Doenças do Íleo/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Interleucina-6RESUMO
To investigate the prognostic role of hTERT expression in non-small cell lung cancer (NSCLC), we examined the expression of hTERT mRNA in tumor specimens from 68 patients with NSCLC using RT-PCR. The expression of hTERT was detected in 34 (50%) of 68 cancer tissues. There were no correlations between hTERT status and any common clinical features except age. Patients with hTERT expression had shorter survival than those without hTERT expression. Multivariate analysis showed that hTERT expression was an independent negative prognostic factor. These results suggest that expression of hTERT may be an independent prognostic factor for NSCLC patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , RNA , Telomerase/metabolismo , Idoso , Análise de Variância , Proteínas de Ligação a DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The neural cell adhesion molecule (N-CAM), a member of the immunoglobulin gene super-family mediating homophilic cell-cell adhesion in a neuroendocrine system, is preferentially expressed in human small cell lung cancer (SCLC). Immunoprecipitation of a panel of SCLC cell lines by monoclonal antibodies (mAbs) specific for N-CAM detects mainly the 145-kDa isoform. This result was correlated with Northern blotting where a single 6.2-kb mRNA was detected in nine SCLC cell lines. To determine cDNA sequence encoding the N-CAM isoform, we selected several cDNA clones encoding N-CAM isolated from OS2-R, a SCLC cell line established in our laboratory. Based on the analysis of the full-length cDNA obtained from two clones, the sequence of this 145-kDa isoform was shown to be essentially identical to that of the 140-kDa N-CAM isoform of neuroblastoma except for a single base pair changed at position 1620 without changing amino acid encoded.