RESUMO
Hand-foot syndrome (HFS) is a common side effect of fluoropyrimidine anticancer drugs and often becomes a dose-limiting manifestation of toxicity once it occurs. The precise mechanism of HFS remains unclear, and effective measures to prevent or relieve it are currently limited. To investigate the pathogenesis of HFS and effective measures for treating or preventing it, establishment of animal models is crucial. Here, we gave male SD rats 170 mg/kg of tegafur (prodrug of 5-FU) daily for 35 days and evaluated their clinical and histopathological characteristics and pain-related behavioral tests. TUNEL-positive apoptotic cells and 5-FU concentrations in the plantar skin were also evaluated to investigate the mode of toxicity. Tegafur treatment induced hypersensitivity to mechanical pressure on the plantar surface beginning in Week 3, with decreased locomotor activity. Focal desquamation of the plantar skin was observed almost concomitantly and gradually worsened to palmar and plantar skin thickening with severe desquamation, cracks, or both. Histopathological lesions in the plantar skin at treatment end included desquamation and thickening, with epidermal cell swelling and spongiosis and focal inflammation in the dermis. The time-course of development and the characteristics of the tegafur-induced skin lesions were highly similar to those in human fluoropyrimidine-induced HFS, indicating that a HFS rat model was successfully established. Localized high concentrations of 5-FU in the palmar and plantar skin, with increased apoptosis, are likely involved in the mode of toxicity. Our model should clarify the pathogenesis of HFS, providing new insights into the best supportive care and prevention.
Assuntos
Antimetabólitos Antineoplásicos , Modelos Animais de Doenças , Síndrome Mão-Pé , Ratos Sprague-Dawley , Tegafur , Animais , Masculino , Tegafur/toxicidade , Ratos , Síndrome Mão-Pé/etiologia , Antimetabólitos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
Dose adjustment based on renal function is essential in S-1, which contains the 5fluorouracil prodrug tegafur, and platinum-based agent oxaliplatin (SOX) combination chemotherapy for colorectal cancer in patients with chronic kidney disease. However, limited evidence on dose adjustment in acute kidney injury (AKI) and challenges in determining dosing strategies. This study investigated the pharmacokinetics of SOX chemotherapy and renal biomarkers in rats.AKI was prepared by renal ischaemia-reperfusion injury in 1,2-dimethylhydrazine-induced colorectal cancer model rats. Serum creatinine (sCr) levels were determined as a renal biomarker. After administration of S-1 (2 mg/kg tegafur) and oxaliplatin (5 mg/kg), drug concentrations of tegafur, 5-FU, and platinum were measured in the plasma and tumours.No alterations in the area under the plasma concentration-time curve (AUC0-24h) values of 5-fluorouracil were observed between control and AKI model rats. The tumour concentrations of 5-fluorouracil in the mild and severe AKI groups were significantly lower than control group. The AUC0-24h for platinum increased with AKI severity. Notably, population pharmacokinetic analysis identified sCr as a covariate in platinum distribution after SOX chemotherapy.To optimise dose adjustment of SOX chemotherapy in patients with AKI, sCr may be a key factor in determining the appropriate dose.
Assuntos
Injúria Renal Aguda , Neoplasias Colorretais , Humanos , Ratos , Animais , Oxaliplatina , Tegafur/toxicidade , Tegafur/farmacocinética , Fluoruracila/uso terapêutico , Fluoruracila/farmacocinética , Rim/patologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required.Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts.Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively.Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.
Assuntos
Tegafur , Animais , Ratos , Tegafur/toxicidadeRESUMO
S-1 is an anticancer agent that consists of tegafur, gimeracil, and oteracil potassium at a molar ratio of 1:0.4:1. S-1 is used to treat metastatic and resectable gastric cancer. However, the extensive use of S-1 in clinical practice results in watery eyes, a serious clinical problem, which worsens patients' quality of life. Although repeated instillation of artificial tears is recommended, therapy or prophylaxis against S-1-induced ocular toxicity has not been established. In the present study, we evaluated the alleviating effects of repeated artificial tear instillation on S-1-induced ocular toxicity in dogs. Ten beagle dogs (5 males and 5 females) were orally administered 3 mg/kg/day of S-1 for up to 21 days. Five drops of artificial tears were instilled to the left eye, eight times daily, within 6 hr after S-1 administration. The mean cornea staining score tended to be low in the left eye with repeated artificial tear instillation. In 4 out of 10 dogs, the corneal staining score of the left eye was more than 2-fold lower than that of the right eye. The incidence of dogs indicating normal tear drainage increased and stenosed tear drainage decreased by repeated artificial tear instillation. In conclusion, we demonstrated that artificial tear instillation can alleviate corneal surface damage induced by S-1 in dogs.
Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Lesões da Córnea/induzido quimicamente , Lesões da Córnea/prevenção & controle , Lubrificantes Oftálmicos/administração & dosagem , Ácido Oxônico/toxicidade , Tegafur/toxicidade , Administração Oftálmica , Animais , Cães , Combinação de Medicamentos , Feminino , MasculinoRESUMO
The development of effective drug screening platforms is an important task for biomedical engineering. Here, a novel methacrylated gelatin (GelMA) hydrogel-encapsulated core-shell photonic crystal (PhC) barcode particle was developed for three-dimensional cell aggregation culture and drug screening. The GelMA shells of the barcode particles enable creation of a three-dimensional extracellular matrix (ECM) microenvironment for cell adhesion and growth, while the PhC cores of the barcode particles provide stable diffraction peaks that can encode different cell spheroids during culture and distinguish their biological response during drug testing. The applicability of this cell spheroids-on-barcodes platform was investigated by testing the cytotoxic effect of tegafur (TF), a prodrug of 5-fluorouracil (5-FU), on barcode particle-loaded liver HepG2 and HCT-116 colonic tumor cell spheroids. The cytotoxicity of TF against the HCT-116 tumor cell spheroids was enhanced in systems using cocultures of HepG2 and NIH-3T3 cells, indicating the effectiveness of this multiple cell spheroids-on-barcodes platform for drug screening.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Células Hep G2 , Humanos , Hidrogéis/química , Camundongos , Células NIH 3T3 , Esferoides Celulares , Tegafur/toxicidadeRESUMO
PURPOSE: To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC). METHODS: Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities. RESULTS: Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR=0.83, 95%CI=0.72-0.96, P=0.01), PFS (HR=0.64, 95%CI=0.56-0.74, P<0.0001), and overall response rate (ORR; RR=2.36, 95%CI=1.73-3.22, P<0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non-hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment. CONCLUSIONS: This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Ácido Oxônico/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Tegafur/administração & dosagem , Antimetabólitos Antineoplásicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Desoxicitidina/administração & dosagem , Desoxicitidina/toxicidade , Intervalo Livre de Doença , Combinação de Medicamentos , Humanos , Ácido Oxônico/toxicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Tegafur/toxicidade , GencitabinaRESUMO
Thymidylate synthase (TS), a target enzyme of 5-fluorouracil (5-FU), is significantly associated with prognosis in various cancers. Recently, it has been reported that S-1, a novel 5-FU-based agent has an effect on bladder cancer. However, in cells with high TS level, S-1 did not have significant effects. Therefore, we examined whether down-regulation of TS enhanced effects of S-1 in them. First, we measured TS level in an aggressive bladder cancer cell line, KU-19-19 by enzyme-linked immunosorbent assay (ELISA) and evaluated its sensitivity to 5-FU using a small interfering RNA (siRNA) for TS. Next, we measured TS mRNA after exposure to various agents. Finally, we evaluated enhancement of cytotoxicity of S-1 by CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) which down-regulated TS in in vivo study. The median TS and dihydropyrimidine dehydrogenase (DPD) level was 53.3 ng/mg and 80.3 ng/mg in KU-19-19 cells, respectively. The 5-FU treatment in KU-19-19 cells transfected with siRNA for TS gene (TYMS) inhibited cell growth more significantly than that for nontargeting control. Down-regulation of TS was observed after exposure to SN-38 (7-ethyl-10-hydroxycamptothecin) in a dose-dependent manner. The combination treatment of 5-FU and SN-38 significantly inhibited cell growth, as compared to the single treatment. Meanwhile, in cells transfected with siRNA for TYMS, neither an additive nor a synergistic effect was observed. Also, combined S-1 and CPT-11 dramatically inhibited tumor growth, compared to S-1 or CPT-11 alone in in vivo study. In conclusion, CPT-11 down-regulated TS level and enhanced the effect of S-1. Thus, the combination therapy with S-1 and CPT-11 might be a novel modality for bladder cancer, even with high TS level.
Assuntos
Camptotecina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ácido Oxônico/farmacologia , Tegafur/farmacologia , Timidilato Sintase/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Animais , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Camptotecina/toxicidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Ácido Oxônico/administração & dosagem , Ácido Oxônico/toxicidade , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Tegafur/administração & dosagem , Tegafur/toxicidade , Timidilato Sintase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently. METHODS: We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m(2), bid) was administered for 3 weeks and cisplatin (60 mg/m(2)) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m(2), bid) was administered for 4 weeks, every 6 weeks. RESULTS: SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively. CONCLUSION: SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/efeitos adversos , Ácido Oxônico/toxicidade , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Tegafur/efeitos adversos , Tegafur/toxicidadeRESUMO
OBJECTIVES: This study was conducted to evaluate the efficacy and safety of S-1, an oral fluoropyrimidine derivative, in Japanese patients with castration-resistant prostate cancer (CRPC). The primary endpoint was prostate-specific antigen (PSA) response. METHODS: In this open-label phase II study, S-1 was started at a dose of 80, 100 or 120 mg daily based on body surface area (BSA) for 28 days, followed by 14 days of rest. Patients with histological proof of prostate cancer refractory to hormonal therapies were eligible. Patients who received prior chemotherapy were excluded. All patients provided written informed consent. To observe 20% confirmed PSA response, 33 assessable patients were needed. Treatment was continued until disease progression or the development of intolerable toxicity. RESULTS: A total of 35 eligible patients were enrolled. The median number of treatment cycles was 3. PSA response was observed in 8 patients (22.9%, 90% CI 11.9-37.5), including 3 in which (8.6%) the PSA level normalized. The median overall survival was 25.4 months. The most common treatment-related grade 3 toxicity was anorexia (14.3%). There was no death during the study. CONCLUSION: S-1 monotherapy is active against castration-resistant prostate cancer and has acceptable toxicity.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Ácido Oxônico/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Tegafur/uso terapêutico , Adulto , Idoso , Alanina Transaminase/sangue , Antagonistas de Androgênios/uso terapêutico , Anorexia/induzido quimicamente , Antimetabólitos Antineoplásicos/toxicidade , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Superfície Corporal , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Tolerância a Medicamentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Orquiectomia , Ácido Oxônico/toxicidade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Segurança , Tegafur/toxicidade , Resultado do TratamentoRESUMO
The combination therapy of CPT-11, a prodrug of SN-38, with S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, shows a high clinical response rate in non-small cell lung cancer (NSCLC). However, this combination causes severe toxicities such as diarrhea. Here, we investigated the advantages of treatment with the SN-38-incorporating polymeric micelles NK012 over CPT-11 in combination with S-1 in mice bearing a NSCLC xenograft in terms of antitumor activity and toxic effects, particularly intestinal toxicity. In vitro cytotoxic effects were examined in human NSCLC cell lines (A549, PC-9, PC-14, EBC-1 and H520). In vivo antitumor effects were evaluated in PC-14- and EBC-1-bearing mice after NK012 or CPT-11 administration on Days 0 and 7 and S-1 administration on Days 0-13. Pathological changes in the small intestine were also investigated. The in vitro growth inhibitory effects of NK012 were 56.8- to 622-fold more potent than those of CPT-11. NK012/S-1 treatment showed significantly higher antitumor activity both in PC-14-bearing (p = 0.0007) and EBC-1-bearing mice (p < 0.0001) than CPT-11/S-1 treatment. The deformity and decrease in the density of intestinal villi were more severe in CPT-11/S-1-treated mice than in NK012/S-1-treated mice. NK012/S-1 combination is a promising candidate regimen against NSCLC without inducing toxicities such as severe diarrhea and therefore warrants clinical evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oxônico/farmacologia , Tegafur/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/toxicidade , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Di-Hidrouracila Desidrogenase (NADP)/biossíntese , Di-Hidrouracila Desidrogenase (NADP)/genética , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Irinotecano , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Ácido Oxônico/administração & dosagem , Ácido Oxônico/química , Ácido Oxônico/toxicidade , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Tegafur/administração & dosagem , Tegafur/química , Tegafur/toxicidade , Timidilato Sintase/biossíntese , Timidilato Sintase/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: The aim of this study was to determine the maximum tolerated dose, recommended dose and dose-limiting toxicities of irinotecan (CPT-11) plus S-1 in advanced colorectal cancer. METHODS: S-1 was administered orally at 80 mg/m(2) per day for 14 consecutive days followed by a 2-week rest. CPT-11 was given intravenously on days 1 and 15 of each course, at an initial dose of 80 mg/m(2) per day, stepping up to 100, 120 or 150 mg/m(2) per day. Courses were repeated every 4 weeks, unless disease progression or severe toxicities were observed. RESULTS: A total of 21 patients were entered in this study. The maximum tolerated dose of CPT-11 was considered to be 150 mg/m(2), because 2 of 3 patients developed dose-limiting toxicities such as leukopenia, neutropenia, diarrhea and anorexia. The recommend dose of CPT-11 was set at 120 mg/m(2). Tumor response rate was 42.8% and median progression-free survival time was 10 months (95% confidential interval, 6.0-14.0 months). CONCLUSION: A combination of S-1 and CPT-11 showed a good safety profile and can be recommended for further phase II studies in patients with colorectal cancer.
Assuntos
Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Ácido Oxônico/toxicidade , Tegafur/toxicidade , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Camptotecina/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgiaRESUMO
BACKGROUND: A transient leukoencephalopathy mimicking cerebrovascular accident has been described as a complication of chemotherapy, most commonly in recipients of intrathecal methotrexate for childhood leukaemia. Recently published neuroimaging data suggest a common pathophysiology associated with a variety of chemotherapy agents and modes of administration. METHODS: We reviewed the medical literature for single reports and case series of patients presenting with stroke-like episodes while receiving systemic or intrathecal chemotherapy. We only included studies providing detailed neuroimaging data. Patients with cerebrovascular accidents were excluded. RESULTS: We identified 27 reports of toxic leukoencephalopathy in patients treated with methotrexate (intrathecal, systemic), 5-fluorouracil and its derivative carmofur, and capecitabine. Diffusion weighted imaging (DWI) of all patients revealed well demarcated hyperintense lesions within the subcortical white matter of the cerebral hemispheres and the corpus callosum, corresponding to areas of decreased proton diffusion on apparent diffusion coefficient (ADC) maps (available in 21/27 patients). Lesions exceeded the confines of adjacent vascular territories. Complete resolution of symptoms within 1-4 days was accompanied by normalisation of ADC abnormalities. However, fluid attenuated inversion recovery (FLAIR) sequences frequently revealed persistent white matter abnormalities. CONCLUSIONS: Several pathophysiological models of delayed leukoencephalopathy after exposure to intrathecal or systemic chemotherapy have been proposed. DWI findings in this cohort are indicative of cytotoxic oedema within cerebral white matter and lend support to an at least partially reversible metabolic derangement as the basis for this syndrome.
Assuntos
Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Demência Vascular/induzido quimicamente , Demência Vascular/diagnóstico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/toxicidade , Metotrexato/toxicidade , Acidente Vascular Cerebral/induzido quimicamente , Tegafur/toxicidade , Adulto , Idoso , Antineoplásicos/uso terapêutico , Encéfalo/patologia , Edema Encefálico/induzido quimicamente , Edema Encefálico/diagnóstico , Capecitabina , Desoxicitidina/uso terapêutico , Desoxicitidina/toxicidade , Imagem de Difusão por Ressonância Magnética , Metabolismo Energético/efeitos dos fármacos , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Infusões Intravenosas , Injeções Espinhais , Imageamento por Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/patologia , Exame Neurológico/efeitos dos fármacos , Sistema de Registros , Remissão Espontânea , Acidente Vascular Cerebral/diagnóstico , Tegafur/uso terapêuticoRESUMO
In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy x 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m(-2) day(-1) on days 1-7 and 15-21 (level 1), 1-14 (level 2), and 1-21 (level 3a) and 80 mg m(-2) day(-1) on days 1-21 (level 3b) and 1-28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19-9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m(-2) day(-1) given on days 1-21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.
Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Ácido Oxônico/toxicidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Radioterapia/métodos , Tegafur/toxicidade , Adulto , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/mortalidade , Análise de SobrevidaRESUMO
We conducted a phase II trial of gemcitabine with S-1, oral fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2, 4-dihydroxypyridine and potassium oxonate, to evaluate the activity and toxicity of such a combination in metastatic pancreatic cancer (MPC) patients. Patients who had pathologically proven pancreatic cancer with metastatic lesions were eligible candidates for entry into the study. S-1 was given orally (30 mg m(-2)) b.i.d. for 14 consecutive days and gemcitabine (1000 mg m(-2)) was given on days 8 and 15. The cycle was repeated every 21 days. We enrolled 33 MPC patients. The median number of cycles was eight (range 1-20). Grade 3-4 toxicities were leucopenia (33%), neutropenia (55%), anaemia (9%), thrombocytopenia (15%), anorexia (6%), fever (9%), and interstitial pneumonia (6%). Objective responses were obtained in 16 patients (one complete response and 15 partial responses; response rate, 48%; 95% confidence interval (CI), 33-65). Median survival and 1-year survival rate were 12.5 months (95% CI, 5.9-19.1) and 54% (95% CI, 36-72), respectively. Combination chemotherapy with GEM and S-1 was well tolerated and yielded a significantly high response rate.
Assuntos
Desoxicitidina/análogos & derivados , Ácido Oxônico/toxicidade , Ácido Oxônico/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Tegafur/toxicidade , Tegafur/uso terapêutico , Idoso , Desoxicitidina/uso terapêutico , Desoxicitidina/toxicidade , Combinação de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Análise de Sobrevida , Fatores de Tempo , GencitabinaRESUMO
BACKGROUND: A combination of irinotecan with continuous intravenous infusions of 5-fluorouracil (5-FU) and leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. This phase II study evaluated the efficacy and safety of the oral fluoropyrimidine S-1 plus irinotecan in patients with previously untreated advanced or recurrent colorectal cancer. PATIENTS AND METHODS: Forty eligible patients with histologically confirmed colorectal adenocarcinoma received this treatment. S-1 was administered orally on days 1 to 14 of a 21-day cycle. Patients were assigned on the basis of body surface area (BSA) to receive one of the following oral doses twice daily: 40 mg (BSA < 1.25 m(2)), 50 mg (BSA > or = 1.25 to < 1.50 m(2)), or 60 mg (BSA > or = 1.50 m(2)). Irinotecan (150 mg/m(2)) was administered by intravenous infusion on day 1. RESULTS: A total of 327 courses of treatment were administered to 40 patients. Five patients had complete responses, and 20 had partial responses. The overall response rate was 62.5% (95% confidential interval, 47.5%-77.5%). Median progression-free survival was 8.0 months (95% confidential interval, 5.2-11.4 months). The rates of grade 3 or 4 toxicity were as follows: neutropenia, 15%; anemia, 7.5%; anorexia, 12.5%; and diarrhea, 7.5%. CONCLUSIONS: Combined treatment with S-1 and irinotecan is an effective, well tolerated, and convenient regimen in patients with advanced colorectal cancer. Our findings suggest that combined treatment with S-1 and irinotecan is a promising regimen, offering benefits in terms of safety and survival as compared with conventional regimens in patients with advanced colorectal cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Anemia/induzido quimicamente , Anorexia/induzido quimicamente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Antineoplásicos Fitogênicos/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/toxicidade , Neoplasias Colorretais/patologia , Diarreia/induzido quimicamente , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Ácido Oxônico/toxicidade , Sobreviventes , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Tegafur/toxicidade , Resultado do TratamentoRESUMO
Diamine oxidase (DAO; EC 1.4.3.6), which catabolizes a variety of substrates including histamine and diamines, is the degradative enzyme of the catabolic pathway of polyamines found in high activity in the mature upper villus cells of the rat intestinal mucosa [Luk, G.D., Bayless, T.M., Baylin, S.B., 1983. Plasma post-heparin diamine oxidase. Sensitive provocative test for quantitating length of acute intestinal mucosal injury in the rat. J. Clin. Invest. 71, 1308-1315; Wolvekamp, M.C.J., de Bruin, R.W.F., 1994. Diamine oxidase: an overview of historical, biochemical and functional aspects. Dig. Dis. 12, 2-14]. Rats were given 1-week repeated oral administration of anti-cancer drugs S-1, containing FT+CDHP+Oxo, and FCD, containing FT+CDHP, and the ameliorating effect of Oxo on the rat gastrointestinal (GI) tract toxicity from 5-FU was evaluated by measuring plasma DAO activity which is related to the enzyme located in the rat intestinal mucosa. Plasma DAO activity in the FCD-treated group was significantly less than that in the S-1-treated group while the jejunal mucosal area in the FCD group was significantly smaller than that in the S-1 group. In addition the histopathological findings in the FCD group showed villus atrophy in the jejunal mucosa which was not observed in the S-1 group. The degree of these findings correlated with the plasma DAO levels. Therefore, the protective effect of Oxo on 5-FU-induced GI tract toxicity was clarified by measuring plasma DAO activity in rats. In summary, DAO is a very sensitive plasma biomarker and will be useful for the quantitative evaluation of the small intestinal mucosal lesions induced by the anti-cancer drug, 5-FU, in rats.
Assuntos
Amina Oxidase (contendo Cobre)/sangue , Biomarcadores/sangue , Doenças do Jejuno/tratamento farmacológico , Administração Oral , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Di-Hidrouracila Desidrogenase (NADP)/antagonistas & inibidores , Fluoruracila/administração & dosagem , Fluoruracila/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Doenças do Jejuno/sangue , Doenças do Jejuno/induzido quimicamente , Masculino , Orotato Fosforribosiltransferase/antagonistas & inibidores , Ácido Oxônico/administração & dosagem , Piridinas/administração & dosagem , Piridinas/toxicidade , Ratos , Ratos Sprague-Dawley , Tegafur/administração & dosagem , Tegafur/toxicidadeRESUMO
We report two cases of gastric carcinoma with successful downstaging using S-1-based chemotherapy followed by surgical resection, which enabled us to confirm the histological effect of chemotherapy. These patients were associated with extensive distant lymph node metastases for which curative resections were unlikely to be performed. We performed anticancer chemotherapy using S-1 with or without concomitant administration of cisplatin in a neoadjuvant setting. After the successful downstaging of these metastatic gastric carcinomas evaluated by imaging analyses, the patients underwent surgical resections. Effect of the chemotherapy was confirmed by the histological analyses. These cases provide further evidence, suggesting that S-1-based chemotherapy enabled downstaging of stage IV gastric carcinoma associated with distant extensive lymph node metastasis and consequently the following possible curative resections. The review of 16 cases of S-1-based chemotherapy followed by surgical resections indicated that, although downstaging may not be expected when N3 lymph node metastases are evident, the S-1-based chemotherapeutic regimens were effective in short cycles for patients in whom potential curative resection is expected. Survival benefit of downstaging followed by surgical resection, however, remains to be further elucidated.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Gastrectomia , Metástase Linfática , Terapia Neoadjuvante , Ácido Oxônico/uso terapêutico , Piridinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Cisplatino/administração & dosagem , Cisplatino/toxicidade , Terapia Combinada , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Feminino , Seguimentos , Gastroscopia , Humanos , Excisão de Linfonodo , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/toxicidade , Piridinas/toxicidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tegafur/toxicidadeRESUMO
BACKGROUND: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. METHODS: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. RESULTS: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 +/- (SE) 0.08, 0.23 +/- 0.13, and 0.09 +/- 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p < 0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). CONCLUSION: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.
Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Absorção Intestinal/efeitos dos fármacos , Tegafur/toxicidade , Animais , Fluoruracila/análogos & derivados , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Ácido Oxônico/toxicidade , Piridinas/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro- and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines. In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation. The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented. The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.
Assuntos
Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/uso terapêutico , Pró-Fármacos/uso terapêutico , Piridinas/uso terapêutico , Tegafur/uso terapêutico , Uracila/uso terapêutico , Administração Oral , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Capecitabina , Desoxicitidina/metabolismo , Desoxicitidina/toxicidade , Fluoruracila/metabolismo , Fluoruracila/toxicidade , Humanos , Neoplasias/tratamento farmacológico , Pró-Fármacos/metabolismo , Pró-Fármacos/toxicidade , Piridinas/metabolismo , Piridinas/toxicidade , Tegafur/metabolismo , Tegafur/toxicidade , Resultado do Tratamento , Uracila/metabolismo , Uracila/toxicidadeRESUMO
S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.