RESUMO
The present retrospective study aimed to evaluate the anti-tumor activity and toxicity of combination chemotherapy with gemcitabine (GEM) and oral S-1 or UFT in patients with advanced or metastatic pancreatic cancer. Ninety-four patients received chemotherapy. Among them, sixty-three were treated with GEM alone, twenty-two with UFT and GEM (UFT/GEM), and nine with S-1 and GEM(S-1/GEM). The median survival time was 8.7 months with GEM, 7.3 months with UFT/GEM, and 23.3 months with S-1/GEM. The overall response rate was 11.1%, 10.0%, and 22.2%, respectively. The 1-year survival rate was 29.5%, 36.4%, and 85.7%, respectively. Although the treatment-related adverse effects were not infrequent in patients treated with S-1/GEM, they were moderate in intensity. The combination chemotherapy with S-1/GEM was well tolerated and yielded a high response rate in patients with pancreatic cancer.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Tegafur/efeitos adversos , Uracila/efeitos adversos , Uracila/uso terapêutico , GencitabinaRESUMO
A 59-year-old woman with a history of abdominal injury was admitted to our hospital for abdominal discomfort. CT revealed a cyst showing a fluid-calcium level in the pancreatic body. EUS-FNA was performed to aspirate the fluid in a cyst. Aspirated was milky-white odorless material. Chemical analysis showed high amylase level in the fluid. Spectroscopic analysis revealed that the fluid mainly consists of calcium phosphate. To the best of our knowledge, this is the first case of milk-of-calcium in a pancreatic pseudocyst with an analysis of cystic fluid obtained by EUS-FNA.
Assuntos
Carbonato de Cálcio/análise , Pseudocisto Pancreático/metabolismo , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Gemcitabine is widely accepted as the first-line agent for advanced pancreatic cancer. The antitumor cell activity of gemcitabine is higher when administered after 5-fluorouracil (5-FU) rather than before 5-FU in an in vitro study. The present study was conducted to define the maximum tolerated dose and dose-limiting toxicity associated with an oral fluoropyrimidine prodrug that combines uracil and tegafur (UFT), given prior to weekly intravenous gemcitabine in patients with advanced pancreatic cancer. METHODS: Over a 21-day cycle, gemcitabine was given intravenously over 30 min on days 8 and 15, while UFT was given orally from days 1 to 14. The dose of UFT used was 400 mg per day, given as two doses. The dose of gemcitabine was escalated in a stepwise fashion from 800 (level 1, n = 3) to 900 mg/m2 (level 2, n = 6) and then to 1,000 mg/m2 (level 3, n = 3), such that totally 12 patients received the combination chemotherapy. RESULTS: During the first cycle, grade 3 leukopenia was observed in 2 patients at dose level 1. Only 1 patient treated at dose level 2 experienced dose-limiting toxicity (grade 3 elevated transaminase), including additional patients treated at this dose level. No grade 3/4 toxicities occurred in patients treated at dose level 3. A significant response was observed in 1 out of 12 patients (8.3%). Seven patients (58.3%) had stable disease, while 4 patients (33.3%) showed disease progression. CONCLUSIONS: The combination chemotherapy of oral UFT and gemcitabine was convenient, well tolerated and may benefit patients with advanced pancreatic cancer. Doses recommended for further study of this schedule are gemcitabine 1,000 mg/m2 and UFT 400 mg/day.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Administração Oral , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pró-Fármacos/efeitos adversos , Tegafur/efeitos adversos , Tegafur/uso terapêutico , Uracila/efeitos adversos , Uracila/uso terapêutico , GencitabinaRESUMO
BACKGROUND: Gemcitabine is a pyrimidine nucleoside analog that is clinically active against pancreatic cancer. We have recently demonstrated that p38 MAPK is specifically activated by gemcitabine and that pharmacological blockade of p38 MAPK signaling prevented gemcitabine-induced apoptosis in human pancreatic cancer cells. In this study, we further investigated the implication of p38 MAPK in the cytotoxic action of gemcitabine. MATERIALS AND METHODS: Cells expressing a dominant-negative mutant of p38 MAPK were generated. Clonogenic assays were used to assess the long-term effect on cancer cell viability in the human pancreatic cancer cells, PK1 and PCI43. The p38 MAPK activation level was assessed using an antibody specific to the phosphorylated form. RESULTS: Gemcitabine increased the activation level of p38 MAPK in a dose-dependent manner and induced apoptosis in the two tested human pancreatic cancer cell lines. The selective p38 MAPK inhibitors, SB203580 and SB202190, reduced gemcitabine-induced activation of p38 MAPK, prevented the gemcitabine-induced apoptosis and increased long-term clonogenic survival. Overexpression of a dominant-negative p38 mutant in cells resulted in the reduction of gemcitabine-induced p38 MAPK activation and apoptosis, and increases in clonogenic survival. CONCLUSION: These results strongly suggest that the activation of p38 MAPK signaling is necessary for gemcitabine-induced cell death in human pancreatic cancer cells. Based upon these results, we suggest that molecules of p38 MAPK signaling pathways should be listed as novel targets for gemcitabine-based therapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/enzimologia , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/antagonistas & inibidores , Desoxicitidina/farmacologia , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Imidazóis/farmacologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , GencitabinaRESUMO
The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.
Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/radioterapia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Cromonas/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Humanos , Imuno-Histoquímica , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação/efeitos da radiação , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt , Tolerância a Radiação/fisiologia , TransfecçãoRESUMO
In this study, we investigated the involvement of Akt and members of the mitogen-activated protein kinase (MAPK) superfamily, including ERK, JNK, and p38 MAPK, in gemcitabine-induced cytotoxicity in human pancreatic cancer cells. We found that gemcitabine induces apoptosis in PK-1 and PCI-43 human pancreatic cancer cell lines. Gemcitabine specifically activated p38 MAPK in a dose- and time-dependent manner. A selective p38 MAPK inhibitor, SB203580, significantly inhibited gemcitabine-induced apoptosis in both cell lines, suggesting that phosphorylation of p38 MAPK may play a key role in gemcitabine-induced apoptosis in pancreatic cancer cells. A selective JNK inhibitor, SP600125, failed to inhibit gemcitabine-induced apoptosis in both cell lines. MKK3/6, an upstream activator of p38 MAPK, was phosphorylated by gemcitabine, indicating that the MKK3/6-p38 MAPK signaling pathway is indeed involved in gemcitabine-induced apoptosis. Furthermore, gemcitabine-induced cleavage of the caspase substrate poly(ADP-ribose) polymerase was inhibited by pretreatment with SB203580, suggesting that activation of p38 MAPK by gemcitabine induces apoptosis through caspase signaling. These results together suggest that gemcitabine-induced apoptosis in human pancreatic cancer cells is mediated by the MKK3/6-p38 MAPK-caspase signaling pathway. Further, these results lead us to suggest that p38 MAPK should be investigated as a novel molecular target for human pancreatic cancer therapies.