RESUMO
KRN 8602 (MX2) is a novel morpholino anthracycline derivative having the chemical structure 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride. To investigate the mechanisms of resistance to MX2, we established an MX2-resistant phenotype (K562/MX2) of the human myelogeneous leukaemia cell line (K562/P), by continuously exposing a suspension culture to increasing concentrations of MX2. K562/MX2 cells were more resistant to MX2 than the parent cells, and also showed cross-resistance to etoposide and doxorubicin. Topoisomerase (Topo) IIalpha protein levels in K562/MX2 cells were lower of those in K562/P cells on immunoblot analysis and decreased expression of Topo IIalpha mRNA was seen in K562/MX2 cells. Topoisomerase II catalytic activity was also reduced in the nuclear extracts from K562/MX2 cells when compared with K562/P cells. Aberrant methylated CpG of Topo IIalpha gene was observed in K562/MX2 cells when compared with the parent line on methylation-specific restriction enzyme analysis. To overcome the drug resistance to MX2 and etoposide, we investigated treatment with 5-Aza-2'-deoxycytidine (5AZ), which is a demethylating agent, in K562/MX2 cells. 5-Aza-2'-deoxycytidine treatment increased Topo IIalpha mRNA expression in K562/MX2 cells, but not in K562/P cells, and increased the cytotoxicity of MX2 and etoposide. Methylated CpG was decreased in K562/MX2 cells after 5AZ treatment. We concluded that the mechanism of drug resistance to MX2 and etoposide in K562/MX2 cells might be the combination of decreased expression of Topo IIalpha gene and increased methylation, and that 5AZ could prove to be a novel treatment for etoposide-resistant cell lines, such as K562/MX2.
Assuntos
Antígenos de Neoplasias/biossíntese , Antineoplásicos/farmacologia , Azacitidina/análogos & derivados , Carrubicina/análogos & derivados , Carrubicina/farmacologia , Metilação de DNA , DNA Topoisomerases Tipo II/biossíntese , Proteínas de Ligação a DNA/biossíntese , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Antígenos de Neoplasias/efeitos dos fármacos , Azacitidina/farmacologia , Northern Blotting , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , DNA Topoisomerases Tipo II/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Decitabina , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Citometria de Fluxo , Humanos , Immunoblotting , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Chronic hepatitis B and C virus infections have been characterized by the pathophysiological features with a high incidence of progression to cirrhosis and development of hepatocellular carcinoma. The viral persistence produced by escape mutations from virus-specific cytotoxic T lymphocytes (CTL) response may lead to upregulation of delayed-type hypersensitivity immune response, which causes hepatic tissue damage through non specific macrophage activation and CTL response and promotes pathogenesis of hepatic fibrosis. In a preliminary clinical study, a novel metalloendopeptidase-F (MEP-F) has been shown to be effective in the treatment of patients with either chronic hepatitis B or C infection. Oral administration of MEP-F resulted in a significant reduction of the serum levels of HBs antigen and HCV RNA and improvement in the liver function abnormalities. However, the mechanism of action of MEP-F is not yet well understood. There are accumulating evidences showing an important role of alpha 2-macroglobulin-proteinase complexes in regulatory mechanisms of immune response and repairing within impaired and inflammatory tissues. In this article, reviewing the pharmacological and biological properties of alpha 2-macroglobulin-proteinase complexes, the mechanism of anti-viral effect of MEP-F is examined based on the clinical findings. It is indicated that alpha 2-macroglobulin-MEP-F complexes may induce macrophage/Kuppfer cell activation and proliferation through binding their receptors on the cells and activating signaling cascades, which enhance both anti-viral specific and nonspecific immune responses. alpha 2-Macroglobulin-MEP-F complexes may also augment cellular immunity and hepatic regeneration by neutralizing the immunosuppressive and fibrogenic activities of transforming growth factor-beta.
Assuntos
Hepatite B Crônica/terapia , Hepatite C Crônica/terapia , Metaloendopeptidases/uso terapêutico , Animais , Citocinas/metabolismo , Citocinas/fisiologia , Hepatite B Crônica/imunologia , Hepatite C Crônica/imunologia , Humanos , Fígado/metabolismo , Fígado/fisiologia , Regeneração Hepática , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Macrófagos/imunologia , Metaloendopeptidases/metabolismo , Metaloendopeptidases/farmacologia , Receptores Imunológicos/metabolismo , Receptores Imunológicos/fisiologia , Linfócitos T Citotóxicos/imunologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , alfa-Macroglobulinas/metabolismo , alfa-Macroglobulinas/fisiologiaRESUMO
To assess the effect of hyperbaric oxygen (HBO) therapy on radiation cystitis, clinical and histopathological characteristics were examined. Three women with radiation cystitis were treated with HBO therapy. Macrohaematuria was arrested in all patients. Cystoscopy demonstrated abnormal telangiectasia and inflammatory mucosa before treatment. After HBO therapy, the inflammatory mucosae were healed. However, abnormal vessels did not completely disappear. Histopathologically, the epithelium was atrophic and dilated lymph vessels and inflammatory cells were seen in the submucosa. These changes improved after treatment. HBO therapy is effective against radiation cystitis. With improvement of the clinical symptoms also the cystoscopic and histopathological findings changed favourably.
Assuntos
Cistite/terapia , Oxigenoterapia Hiperbárica , Lesões por Radiação/terapia , Bexiga Urinária/patologia , Idoso , Cistite/etiologia , Cistite/patologia , Feminino , Humanos , Mucosa/patologia , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Bexiga Urinária/efeitos da radiaçãoRESUMO
Gallic acid (GA) and chebulagic acid (CA) were isolated from the extract of a herbal medicine, kashi (myrobalans: the fruit of Terminalia chebula) as active principles that blocked the cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. GA and CA inhibited the killing activity of CD8+ CTL clone at IC50 values of 30 microM and 50 microM, respectively. Granule exocytosis in response to anti-CD3 stimulation was also blocked by GA and CA at the equivalent concentrations.
Assuntos
Benzopiranos/farmacologia , Inibidores Enzimáticos/farmacologia , Ácido Gálico/farmacologia , Glucosídeos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Linfócitos T Citotóxicos/imunologia , Animais , Benzopiranos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Inibidores Enzimáticos/isolamento & purificação , Ácido Gálico/isolamento & purificação , Glucosídeos/isolamento & purificação , CamundongosRESUMO
We report a 50-year-old Japanese woman with a 3-year history of systemic lupus erythematosus treated with prednisolone, who had diffuse plane yellowish macules mainly on the upper arm. The lesion was clinically diagnosed as diffuse plane xanthomatosis. However, the histopathological findings from both the yellowish macules and the normal-appearing skin revealed a heavy degeneration of collagen fibers with membranocystic structure throughout the entire dermis and the collagenous septum of the subcutaneous tissue. Ultrastructurally, the membranocystic structure was not due to the degenerative change of fat cells as seen in membranous lipodystrophy but was caused by the degenerative change of collagen fibers with fat deposit.
Assuntos
Anti-Inflamatórios/uso terapêutico , Colágeno , Glucocorticoides/uso terapêutico , Lúpus Eritematoso Sistêmico/patologia , Prednisolona/uso terapêutico , Xantomatose/patologia , Braço/patologia , Colágeno/ultraestrutura , Tecido Conjuntivo/patologia , Feminino , Humanos , Metabolismo dos Lipídeos , Lipodistrofia/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Microscopia Eletrônica , Pessoa de Meia-Idade , Pele/patologiaRESUMO
The nonapeptide leucinostatin A (LSA) inhibited syncytium formation without profoundly affecting HN glycoprotein synthesis in Newcastle disease virus (NDV)-infected BHK cells. At similar doses of LSA, cytopathic effect and infectious virus production were suppressed in vesicular stomatitis virus (VSV)-infected BHK cells. Blockade by LSA of cell surface expression of NDV-HN and VSV-G glycoproteins was demonstrated, accompanied by intracellular accumulation of these virus glycoproteins. LSA acts as an inhibitor of mitochondrial F-type H(+)-translocating ATPase, a key enzyme in the generation of ATP, but its action against cell surface expression of virus glycoproteins was independent of the depletion of intracellular ATP. LSA also acts as an ionophore, but its action on intoxication by ricin and diphtheria toxin was different from that of monensin. This novel action of LSA is expected to be useful in investigation of the mechanism of intracellular trafficking of proteins.
Assuntos
Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Rim/efeitos dos fármacos , Rim/virologia , Glicoproteínas de Membrana/biossíntese , Vírus da Doença de Newcastle/efeitos dos fármacos , Peptídeos , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Proteínas Virais/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos , Células Cultivadas , Cricetinae , Ionóforos/farmacologia , Glicoproteínas de Membrana/efeitos dos fármacos , Vírus da Doença de Newcastle/metabolismo , Vírus da Estomatite Vesicular Indiana/metabolismo , Proteínas Virais/biossínteseRESUMO
The inhibitory effect of KRN5500, a spicamycin derivative, on the growth of hepatic metastasis of the tissue polypeptide antigen (TPA)-producing human colon cancer COL-1 was examined in severe combined immunodeficient (SCID) mice. Prior to this chemotherapeutic study, we confirmed the high correlation coefficient (r = 0.86, P < 0.01) between plasma TPA levels in athymic nude mice bearing COL-1 and tumor volume. In the chemotherapy of experimental hepatic metastasis induced by intrasplenic injection of COL-1 cells, KRN5500 at 12 mg/kg per day was administered i.v. three times at 4-day intervals. From the start of chemotherapy (day 1), plasma TPA levels in the mice were significantly decreased from 8332 U/l to a minimum of 494 U/l on day 16 and were within the range for intact SCID mice (409-634 U/l). The mean tumor weight was 4.87 g in the liver of untreated mice on day 19 and 0.74 g, in the liver of KRN5500-treated mice, a significant difference, representing a tumor growth inhibition rate of 85%. These results suggest the usefulness of TPA as a tumor marker in an experimental xenograft model. The chemotherapeutic efficacy of KRN5500 against experimental hepatic metastasis indicates that it may be a useful drug for the treatment of patients with hepatic metastases of colon cancer.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias do Colo/tratamento farmacológico , Neoplasias Hepáticas/secundário , Antígeno Polipeptídico Tecidual/efeitos dos fármacos , Animais , Feminino , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos SCID , Tamanho do Órgão , Nucleosídeos de Purina/química , Nucleosídeos de Purina/uso terapêutico , Antígeno Polipeptídico Tecidual/sangueRESUMO
New derivatives of spicamycin modified at the fatty acid moieties of the molecule were synthesized and their structure-activity relationships were examined. The antitumor activity was greatly influenced by modification of the fatty acid moieties to tetradecadienoyl or dodecadienoyl analogues exhibiting better antitumor activity against COL-1 human colon cancer xenograft than SPM VIII.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Animais , Antibióticos Antineoplásicos/biossíntese , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Nucleosídeos de Purina/biossíntese , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Streptomyces/metabolismo , Relação Estrutura-AtividadeRESUMO
Costunolide and dehydrocostus lactone were isolated from an extract of mokko (Saussurea lappa Clarke) as inhibitors of killing activity of cytotoxic T lymphocytes (CTL). Mokko lactone was also isolated as an inactive compound from the extract. The structure-activity relationship indicated that alpha-methylene-gamma-butyrolactone is required for the inhibitory effect. Costunolide markedly inhibited the granule exocytosis and the production of inositol phosphates in response to anti-CD3 monoclonal antibody (mAb) stimulation at a concentration that did not affect the binding of anti-CD3 mAb. Tyrosine phosphorylation induced by crosslinking of CD3 molecules was significantly inhibited by costunolide in a dose-dependent manner. These results suggest that costunolide inhibits the killing activity of CTL through preventing the increase in tyrosine phosphorylation in response to the crosslinking of T-cell receptors.
Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Lactonas/farmacologia , Sesquiterpenos/farmacologia , Linfócitos T Citotóxicos/imunologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Fosforilação , Linfócitos T Citotóxicos/metabolismo , Tirosina/metabolismoRESUMO
A series of SPM VIII analogs were synthesized to investigate the effect of the amino acid moiety on the antitumor activity. The L-threonine analog and the glycylglycine analog of SPM VIII showed much higher cytotoxicity to P388 murine leukemia cells (IC50 5.8 nM and 0.11 nM, respectively) than SPM VIII (IC50 25nM). However, replacement of the glycine moiety with other amino acids greatly reduced the antitumor activity against COL-1 human colon cancer xenograft model. This study indicated that the glycine moiety of SPM VIII is crucial for the antitumor effect.
Assuntos
Antibióticos Antineoplásicos/síntese química , Aminoácidos/farmacologia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Feminino , Humanos , Leucemia P388/tratamento farmacológico , Camundongos , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Nucleosídeos de Purina/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Six cases of ureteral injuries were analyzed. Two cases were male and 4 cases were female. The right side was affected in 1 case and the left in 5 cases. The affected portion was the uretero-pelvic junction in 1 case and lower iliac vessels in the other cases. Five cases were iatrogenic injuries in surgical or gynecological pelvic operation, and the other was due to blunt trauma. Intraoperative diagnosis was made in 4 cases. Drain leakage led to diagnosis in one case and pyelonephritis in another. Ureteroureterostomy was performed in 2 cases, pyeloureterostomy in 1 case, ureteroneocystostomy with psoas hitch in 1 case, Boari bladder flap in 1 case and simple suture in 1 case. 4-0 or 5-0 Dexon with an atraumatic needle was used for all anastomoses. Except for case 1, who died of the recurrence of carcinosarcoma, renal functions were preserved in all patients during the follow-up period ranging from 5 months to 7 years 8 months.
Assuntos
Exenteração Pélvica/efeitos adversos , Ureter/lesões , Ureter/cirurgia , Adulto , Idoso , Colectomia/efeitos adversos , Feminino , Humanos , Histerectomia/efeitos adversos , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Obstrução Ureteral/etiologia , Ureterostomia , Ferimentos não Penetrantes/complicaçõesRESUMO
The antitumor activity of spicamycin analogue SPM VIII against human stomach, breast, lung, colon and esophageal cancers was compared to that of mitomycin C (MMC) in the human tumor-nude mice xenograft model. Comparative studies of SPM VIII given i.v. at 6 mg/kg/day daily for 5 days and MMC given i.v. at 6.7 mg/kg on day 1 revealed that the antitumor spectrum of SPM VIII showed a different pattern from that of MMC and that SPM VIII caused tumor mass reductions in more tumors than did MMC in colon cancers (4/12 versus 1/11). In addition to this study, a comparative study of SPM VIII given i.v. at 12 mg/kg/day 8 times at 3- or 4-day intervals and 5'-deoxy-5-fluorouridine (5'-DFUR) given po at 185 mg/kg/day 5 days per week for 4 weeks showed that SPM VIII had the highest effect on SC-9 human stomach cancer and COL-1 human colon cancer among the 3 compounds, resulting in a significant reduction of tumor mass. Although other pharmacological studies are in progress, these results suggest that SPM VIII might be a novel antitumor compound effective for human cancers including cancer of the digestive organs.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Animais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitomicina/uso terapêutico , Transplante de Neoplasias , Nucleosídeos de Purina/uso terapêutico , Transplante HeterólogoRESUMO
Spicamycin, a nucleoside antibiotic containing fatty acids with a variety of chain lengths (C12-C18), showed potent antitumor activity against human gastric cancer SC-9 and human breast cancer MX-1 in a xenograft model. We have made several semi-synthetic spicamycin analogues (SPMs) which differed in the chain length of the fatty acid moiety, and examined their structure-antitumor activity relationship. The cytotoxic activities of SPMs depended on the chain length of the fatty acid moiety, with dodecanoyl, tetradecanoyl, hexadecanoyl and icosanoyl analogues (SPM VIII, SPM X, SPM XII and SPM XVI) exhibiting the most potent cytotoxic activity against P388 murine leukemia cells. SPM VIII showed the most activity against SC-9 in the human tumor xenograft model with the highest therapeutic index among SPMs. The antitumor activity of SPM VIII was superior to that of mitomycin C.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Leucemia P388/tratamento farmacológico , Leucemia P388/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Transplante de Neoplasias , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologia , Nucleosídeos de Purina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A 58-year-old man with basal cell nevus syndrome had variously sized basal cell epitheliomas (BCEs), mostly of the superficial type, on his chest, back, and lumbar areas. BCEs on the lumbar area were treated with 5-fluorouracil (5-FU) cream which was applied daily under occlusive dressings (ODT). Complete erosion occurred in the center, but not at the periphery of the lesions. In the latter regions, BCE remained. Then cryosurgery (cryo) followed by topical 5-FU (cryo + 5-FU) was tried to treat the peripheral, non-eroded lesions; this caused complete erosions. Biopsy specimens obtained 6 months after epithelization did not show any evidence of recurrence. We also tried either cryo alone or cryo + 5-FU on the chest lesions, and either 5-FU alone or cryo + 5-FU on the abdominal lesions. Cryo alone or 5-FU alone could not clear BCE, but cryo + 5-FU could. These results suggest that the cryo + 5-FU was the most effective of these therapies.
Assuntos
Síndrome do Nevo Basocelular/terapia , Carcinoma Basocelular/terapia , Criocirurgia , Fluoruracila/administração & dosagem , Neoplasias Primárias Múltiplas , Neoplasias Cutâneas/terapia , Administração Tópica , Dorso , Síndrome do Nevo Basocelular/patologia , Carcinoma Basocelular/patologia , Terapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Curativos Oclusivos , Pele/patologia , Neoplasias Cutâneas/patologia , TóraxRESUMO
Gilvocarcin V was chemically transformed to alter its biological activities as well as its solubility by mainly focusing on the vinyl side chain. The oxirane and oxime derivatives showed slightly decreased in vivo antitumor activity, while the aminoethylmorpholine derivative turned out to be soluble in some organic solvents.
Assuntos
Aminoglicosídeos , Antibacterianos/química , Antibióticos Antineoplásicos/química , Animais , Antibacterianos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Cumarínicos , Glicosídeos , Leucemia P388/tratamento farmacológico , Camundongos , SolubilidadeRESUMO
We herein report a case of a rare variety of the acute eruptive form of lichen planus. The patient was a 51-year-old male who developed an intensely pruritic eruption on the lower legs which spread rapidly to all four extremities and trunk within a few months. The papulosquamous lesions were more than ten thousand in number. Topical steroid, cyclosporine, and systemic griseofulvin treatments were ineffective. However, there was a dramatic response to oral etretinate.
Assuntos
Líquen Plano/patologia , Etretinato/uso terapêutico , Humanos , Líquen Plano/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
4'-O-Acyl derivatives of doxorubicin, daunorubicin, 13-deoxocarminomycin, 13-deoxo-10-hydroxycarminomycin, 13-deoxo-11-deoxycarminomycin were synthesized through the formation and mild acid hydrolysis of 2-oxazoline intermediates. The antitumor activity of these 4'-O-acyl derivatives against P388 leukemia was similar to or more effective than the parent anthracyclines.
Assuntos
Antibióticos Antineoplásicos/síntese química , Antineoplásicos/síntese química , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Leucemia P388/tratamento farmacológico , CamundongosRESUMO
Methods for determining concentrations of a new morpholino anthracycline MX2.HCl and its metabolites in biological samples using reversed-phase high-performance liquid chromatography and fluorescence detection are described. The limits of detection were less than 1 ng/ml for all compounds after extraction from 0.5 ml of plasma using C18 Sep-Pak cartridges and consecutive solvent extraction. The recoveries from rat plasma ranged from 72.0 to 89.3%. The peak-height ratio of the fluorescence intensities of these compounds versus internal standard showed a linear correlation for concentrations up to at least 500 ng/ml in the plasma (correlation coefficient r greater than 0.999). The within-day and between-day precisions of this assay were in the range 0.8-8.7% (n = 5) and 2.0-3.5% (n = 5), respectively. The concentrations of these compounds in the blood and urine can be also determined by a slight modification of the extraction procedure.