RESUMEN
In human amyloidoses, amyloid signature proteins (ASPs), such as serum amyloid P component (SAP) and apolipoprotein E (ApoE), are deposited in tissues together with amyloid fibrils and are implicated in the pathogenesis of amyloidosis. Few reports describe ASPs in animals. In this study, we examined feline amyloidosis and performed immunohistochemical and proteomic analyses of SAP, ApoE, apolipoprotein A-I (ApoAI) and apolipoprotein A-IV (ApoAIV). Ten cases of systemic amyloidosis, three cases of amyloid-producing odontogenic tumour and three cases of islet amyloidosis were used for immunohistochemistry (IHC) and/or proteomic analyses. IHC showed that ApoE was present in amyloid deposits in all samples. ApoAI and ApoAIV differed in the degree of co-deposition with amyloid depending on the type of amyloid and the affected organ. SAP was negative in all amyloid deposits. Proteomic analysis showed that ApoE was present in all samples, but ApoAI and ApoAIV were detected only in some samples and SAP was not detected in any samples. The observation that ApoE was detected in all types of amyloid suggests the involvement of ApoE in the development of feline amyloidosis. ASPs in feline amyloidosis are significantly different from those in human amyloidosis, suggesting that the involvement of ASPs in the pathological condition differs between animal species.
Asunto(s)
Amiloidosis/veterinaria , Enfermedades de los Gatos , Amiloide/metabolismo , Amiloidosis/patología , Animales , Apolipoproteína A-I/metabolismo , Apolipoproteínas A/metabolismo , Apolipoproteínas E/metabolismo , Gatos , Inmunohistoquímica/veterinaria , Placa Amiloide/veterinaria , ProteómicaRESUMEN
A 1-year-old pregnant Yorkshire gilt was found dead with no previous clinical signs. Gross findings included metritis, splenomegaly, and valvular endocarditis. Bacterial endocarditis (in the mitral and tricuspid valves) and metritis with dissemination to multiple organs was diagnosed by using histologic examination. Gram-negative coccobacillary organisms present in the valvular lesions were characterized as Actinobacillus equuli by using polymerase chain reaction examination on formalin-fixed, paraffin-embedded tissues (FFPE). A. equuli is rarely reported as a cause of septicemia in pigs in Europe. A. equuli in pigs in the United States has been reported only twice and not, to our knowledge, in the last 30 years. This is the first time that molecular techniques have been used to characterize this organism in FFPE porcine tissues.
Asunto(s)
Infecciones por Actinobacillus/veterinaria , Actinobacillus equuli/aislamiento & purificación , Endocarditis Bacteriana/veterinaria , Enfermedades de los Porcinos/microbiología , Enfermedades Uterinas/veterinaria , Infecciones por Actinobacillus/microbiología , Infecciones por Actinobacillus/patología , Actinobacillus equuli/genética , Animales , Secuencia de Bases , ADN Bacteriano/química , ADN Bacteriano/genética , Endocarditis Bacteriana/microbiología , Endocarditis Bacteriana/patología , Resultado Fatal , Femenino , Histocitoquímica/veterinaria , Datos de Secuencia Molecular , Embarazo , ARN Ribosómico 16S/química , ARN Ribosómico 16S/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Sepsis/microbiología , Sepsis/patología , Sepsis/veterinaria , Enfermedades de los Porcinos/patología , Enfermedades Uterinas/microbiología , Enfermedades Uterinas/patologíaRESUMEN
Adult rabbits were inoculated with liver homogenate from a rabbit that died in a Japanese outbreak of rabbit haemorrhagic disease (RHD). All experimentally infected rabbits died with typical clinical, gross and histological findings of RHD. Distribution of RHD virus in tissues of the infected rabbits was studied by non-isotopic in-situ hybridization. Both viral plus- and minus-strand RNAs were detected within the cytoplasm of hepatocytes, Kupffer cells and splenic and alveolar macrophages, mainly in morphologically intact cells. Strand-specific reverse transcriptase-polymerase chain reaction also demonstrated viral minus-strand RNA as well as plus-strand RNA in the liver, lung and spleen of infected rabbits. These results suggest that viral replication occurs not only in hepatocytes but also in macrophages. The infected macrophages may contribute to viral dissemination in RHD.
Asunto(s)
Infecciones por Caliciviridae/veterinaria , Virus de la Enfermedad Hemorrágica del Conejo/aislamiento & purificación , ARN Viral/análisis , Conejos/virología , Animales , Infecciones por Caliciviridae/patología , Infecciones por Caliciviridae/virología , Clonación Molecular , Femenino , Virus de la Enfermedad Hemorrágica del Conejo/genética , Hepatocitos/patología , Hepatocitos/virología , Hibridación in Situ/veterinaria , Macrófagos del Hígado/patología , Macrófagos del Hígado/virología , Hígado/patología , Hígado/virología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Bazo/patología , Bazo/virología , Replicación ViralRESUMEN
DX-8951f, a new water-soluble camptothecin (CPT) derivative, has been reported to show potent antitumor effects against various tumors in vitro and in vivo. We further evaluated the cytotoxic effect of DX-8951f against eight drug-resistant sublines derived by stepwise exposure of human oat cell carcinoma PC-6 to various drugs. In paclitaxel-, adriamycin-, vincristine- and etoposide-resistant cells, overexpression of P-glycoprotein (P-gp) and a correlative reduction in drug accumulation and typical drug-sensitivity pattern were confirmed. The etoposide-resistant line with the highest P-gp level was cross-resistant also to SN-38, CPT-11 and topotecan (TPT), but not to 9-aminocamptothecin (9-AC), CPT and DX-8951f. SN-38- and CPT-11-resistant cells, of which topoisomerase I activities and levels were similar to those of the parent cells, showed cross-resistance clearly to TPT, 9-AC and mitoxantrone, but hardly to DX-8951f. In these two resistant sublines, the intracellular topotecan level was significantly lower than that in parental PC-6 and the reduced accumulation was found to be mediated by breast cancer resistant protein (BCRP). The cisplatin-resistant variant, which had a 2-fold increase in glutathione content, showed no cross-resistance and the 5-fluorouracil-resistant variant, which had a 50% decrease in glutathione content, exhibited collateral sensitivity to most of the other anticancer agents including DX-8951f. We concluded that DX-8951f showed a potent cytotoxic effect on various types of drug-resistant cells.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/metabolismo , Western Blotting , Carcinoma de Células Pequeñas/metabolismo , Cisplatino/farmacología , Cartilla de ADN/química , ADN-Topoisomerasas de Tipo I/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Estabilidad de Medicamentos , Fluorouracilo/farmacología , Glutatión/metabolismo , Gutatión-S-Transferasa pi , Glutatión Transferasa/metabolismo , Humanos , Técnicas In Vitro , Inactivación Metabólica , Isoenzimas/metabolismo , Neoplasias Pulmonares/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidores de Topoisomerasa I , Tubulina (Proteína)/metabolismo , Moduladores de TubulinaRESUMEN
Novel pyrimidinyl pyrazole derivatives were synthesized and examined for cytotoxic and antitumor activity. Mannich reaction was employed to construct this scaffold. Among the compounds synthesized, a series of propene derivatives exhibited a potent cytotoxic activity against some tumor cell lines including multidrug resistant cell lines due to the overexpression of P-glycoprotein. The vinyl bond moiety in the scaffold was believed to be required for the cytotoxic activity. Among them, compound 14 g, when administered intraperitoneally, showed potent antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice. This compound also showed high activity against a solid tumor Meth A mouse fibrosarcoma when administered both intraperitoneally and orally.
Asunto(s)
Antineoplásicos/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Trasplante de Células , Fibrosarcoma/tratamiento farmacológico , Humanos , Leucemia P388/tratamiento farmacológico , Ratones , Pirazoles/farmacología , Pirimidinas/farmacología , Relación Estructura-Actividad , Trasplante Homólogo , Células Tumorales CultivadasRESUMEN
To develop non-prodrugs of taxoids with satisfactory stability in vivo, high water-solubility, and potent antitumor activity, we prepared several 10-O-sec-aminoethyl docetaxel analogs (3) and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines, microtubule disassembly-inhibitory activity, and water-solubility. These analogs were synthesized from the 10-O-allyl baccatin derivatives (5a-c) using the beta-lactam synthon method. Among these analogs, the 10-O-(2-morpholinoethyl) (18, 21) and 10-O-(2-thiomorpholinoethyl) (19, 24) analogs exhibited cytotoxicity comparable or superior to that of docetaxel (2). In addition, the methanesulfonic acid salt (18a) had a high water-solubility.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Paclitaxel/análogos & derivados , Taxoides , Animales , Antineoplásicos Fitogénicos/farmacología , Fenómenos Químicos , Química Física , Docetaxel , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Paclitaxel/síntesis química , Paclitaxel/farmacología , Solubilidad , Porcinos , Tubulina (Proteína)/química , Tubulina (Proteína)/aislamiento & purificaciónRESUMEN
Nineteen ring A- and F-modified hexacyclic analogues of camptothecin were synthesized by Friedländer condensation of appropriately substituted bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of the compounds showed cytotoxic effects comparable or superior to those of 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 and human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, methoxy, chloro, or fluoro group into position 5 of ring A of the hexacyclic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlation with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyclic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.
Asunto(s)
Antineoplásicos/síntesis química , Camptotecina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Inhibidores de Topoisomerasa I , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/síntesis química , Camptotecina/química , Camptotecina/farmacología , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Irinotecán , Leucemia P388/patología , Ratones , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
An alkylation method of docetaxel at the C-10 position has been established by a radical coupling reaction using a 10-xanthate derivative of 7-O-TES-10-deacetylbaccatin III and appropriate alkenes. In addition the cytotoxic activity of 10-alkylated docetaxel analogs was evaluated. Among these analogs, a derivative having a methoxycarbonyl group at the end of the alkyl moiety exhibited more potent cytotoxic activity than docetaxel.
Asunto(s)
Paclitaxel/análogos & derivados , Taxoides , Alquilación , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Docetaxel , Modelos Moleculares , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/farmacología , Células Tumorales CultivadasRESUMEN
To investigate the role of the 2'-hydroxy group at the C-13 side chain of docetaxel in the antitumor activity, we prepared several 2',2'-difluoro derivatives of docetaxel and evaluated their cytotoxicity against mouse leukemia and human tumor cell lines and their microtubule disassembly-inhibitory activity. These analogues were prepared by esterification of protected 10-deacetylbaccatin III (21) with appropriate alpha, alpha-difluorinated carboxylic acids (Charts 1 and 2). Among these 2',2'-difluorodocetaxel derivatives, 2',2'-difluorodocetaxel (23b) was approximately 3-10 times as active as 2'-fluorodocetaxel (29a) in terms of cytotoxicity. In addition, the 3'-(2-furyl) (23h) and 3'-(2-pyrrolyl) (23p) analogues showed activity comparable or superior to that of docetaxel (2).
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Paclitaxel/análogos & derivados , Taxoides , Animales , Antineoplásicos Fitogénicos/química , Colorantes , Cristalografía por Rayos X , Docetaxel , Humanos , Espectrometría de Masas , Ratones , Microtúbulos/efectos de los fármacos , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/farmacología , Relación Estructura-Actividad , Porcinos , Sales de Tetrazolio , Tiazoles , Tubulina (Proteína)/química , Tubulina (Proteína)/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
Novel benzophenone derivatives were synthesized and screened for cytotoxic and antitumor activity. Friedel-Crafts condensation was employed to construct the benzophenone skeleton. Among the compounds synthesized, morpholino and thiomorpholino benzophenones 3a-d exhibited potent cytotoxic activity against P388 murine leukemia and PC-6 human lung carcinoma cells in vitro, and compounds 3a, 3c, and 3j, when administered intraperitoneally, showed significant antitumor activity against the malignant ascites caused by intraperitoneal inoculation of P388 cells in mice.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzofenonas/síntesis química , Benzofenonas/farmacología , Animales , División Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Células Tumorales CultivadasRESUMEN
We previously reported that DX-8951f, a novel water-soluble camptothecin analog, significantly inhibits the growth of various human and murine tumors in vitro and in vivo. The antitumor effects and topoisomerase I inhibitory activity of DX-8951f are stronger than those of other current camptothecin analogs. In this study, we established an SN-38-resistant cell line, PC-6/SN2-5, from the human oat cell carcinoma PC-6 cell line by a stepwise selection system, investigated the mechanism of resistance of this cell line and then compared the antitumor activity of camptothecin analogs against the cell line. PC-6/SN2-5 cells were resistant to SN-38 (32-fold) and SK&F 104864 (topotecan; 14-fold), but barely resistant to CPT-11 (3-fold) and DX-8951f (2-fold). Topoisomerase I protein levels and topoisomerase I activities of parental cells were similar to those of resistant cells. Determination of the cellular drug concentration by either flow cytometric analysis or the high-performance liquid chromatography method confirmed that the cellular accumulation of SN-38 and topotecan was significantly reduced in PC-6/SN2-5 cells, whereas that of DX-8951f was only slightly reduced. Furthermore, DX-8951f stabilized the cleavable complex formations in intact PC-6/SN2-5 cells as well as in parental cells, but SN-38 and topotecan did not in the resistant cells. Our data suggest that PC-6/SN2-5 cells may have acquired resistance to camptothecin analogs by a decrease in intracellular drug accumulation and that DX-8951f may have the potency to overcome such a type of resistance mechanism induced by camptothecin compounds.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos Fitogénicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/farmacología , Carcinoma de Células Pequeñas/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , ADN de Neoplasias/metabolismo , Resistencia a Antineoplásicos , Estabilidad de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Citometría de Flujo , Humanos , Irinotecán , Neoplasias Pulmonares/metabolismo , Solubilidad , Inhibidores de Topoisomerasa I , Topotecan , Células Tumorales Cultivadas , AguaRESUMEN
PURPOSE: To evaluate the effectiveness of positron emission tomography (PET) with carbon-11 choline in brain tumor imaging. MATERIALS AND METHODS: A rat glioma cell line (C6) was incubated with C-14 choline; the time course of uptake and metabolism was determined in vitro. C-11 choline was injected intravenously in tumor-bearing rats; the time course of distribution in organs was determined. C-11 choline also was injected intravenously in 20 patients (aged 6-86 years) with brain tumors and two volunteers (aged 38 and 58 years); distribution of the tracer in the brain was determined. Regional cerebral blood flow was measured by using oxygen-15 water on the same day. RESULTS: C-14 choline was metabolized to phosphoryl choline in glioma cells. The uptake of C-11 choline by glioblastoma cells was three to four times higher than that in the rat brain. All brain tumors took up more C-11 choline than did normal brain; thus, brain tumors that were not treated, as well as those that were treated with surgery or radiation therapy, were depicted. The tumor-normal brain uptake ratio of C-11 choline in brain tumor did not correlate with the O-15 water regional blood flow in the corresponding area. CONCLUSION: C-11 choline PET can depict brain tumors effectively. This method was clinically useful in patients who had undergone surgery.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Colina , Tomografía Computarizada de Emisión , Adulto , Anciano , Animales , Neoplasias Encefálicas/metabolismo , Niño , Colina/farmacocinética , Femenino , Glioma/diagnóstico por imagen , Glioma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos de Oxígeno , Ratas , Ratas Sprague-Dawley , Células Tumorales CultivadasRESUMEN
Antitumor activities of liposomes containing adriamycin (L-ADM) and their distribution process into tumour cells were analysed. The lipid composition of the liposomes was dimyristoylphosphatidylglycerol (DMPG)/egg phosphatidylcholine/cholesterol/adriamycin (ADM) in a molar ratio of 11.4:2:12:1.3. Liver-metastasizing murine tumour models, M5076 and L5178Y-ML, were used. In vivo antitumour effect against these tumour models was assessed from increase in life span (ILS). The survival prolongation effect of L-ADM in mice with liver failure caused by M5076 was significantly higher than that of F-ADM. In contrast, significant enhancement of the effects by encapsulation in liposomes was not observed in L5178Y-ML-bearing mice. In vitro cytostatic activities of L-ADM against M5076 cells as well as against other tumour cell lines were lower than those of F-ADM. The in vitro kinetic study on the distribution of L-ADM to the tumour cells revealed that ADM in L-ADM was taken up into the tumour cells mainly after it was released from the liposomes rather than taken up as the liposomal form. Among the cell lines tested, M5076 cells had the highest phagocytic activity and therefore the highest uptake activity of ADM during incubation with L-ADM. These findings suggest that the augmented antitumour activity of L-ADM in M5076-bearing mice was the result of phagocytosis of L-ADM by M5076 cells as well as the reduction of toxicity, prolonged retention of ADM in systemic circulation, and liver accumulation of ADM after administration of L-ADM.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/secundario , Animales , Antibióticos Antineoplásicos/farmacocinética , Medios de Cultivo , Modelos Animales de Enfermedad , Doxorrubicina/farmacocinética , Composición de Medicamentos , Estabilidad de Medicamentos , Sarcoma Histiocítico/tratamiento farmacológico , Sarcoma Histiocítico/metabolismo , Sarcoma Histiocítico/patología , Humanos , Leucemia P388/tratamiento farmacológico , Leucemia P388/metabolismo , Leucemia P388/patología , Liposomas , Neoplasias Hepáticas Experimentales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
A 78-year-old man was admitted to our hospital in October 1994 because of renal dysfunction. The level of anti-myeloperoxidase antibody in serum was 500 EU/ml, and examination of a specimen obtained by open renal biopsy revealed crescentic glomerulonephritis. A chest roentgenogram revealed no abnormality. Administration of prednisolone was started at 50 mg/day, and the dosage was then tapered. Renal function remained stable, but on interstitial shadow appeared on the chest roentgenogram. Pulmonary function tests showed a restrictive ventilatory abnormality and a low diffusing capacity. A thoracoscopic lung biopsy was done in April 1995, and microscopic examination of the specimen showed interstitial pneumonia with relatively young granulation. The dosage of prednisolone was increased to 50 mg/day, after which the interstitial shadow decreased and pulmonary function improved. The level of anti-myeloperoxydase antibody in serum was 16 EU/ml (weakly positive). Alveolar hemorrhage can occur in cases of rapidly progressive glomerulonephritis. In addition, interstitial pneumonia or pulmonary fibrosis can also complicate this condition. In the present case, glomerulonephritis associated with anti-myeloperoxydase antibody co-existed with interstitial pneumonia. This case is valuable because both renal biopsy and lung biopsy specimens were available.
Asunto(s)
Autoanticuerpos/sangre , Glomerulonefritis/complicaciones , Enfermedades Pulmonares Intersticiales/etiología , Peroxidasa/inmunología , Anciano , Progresión de la Enfermedad , Glomerulonefritis/inmunología , Humanos , MasculinoRESUMEN
CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Camptotecina/química , Camptotecina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Solubilidad , Inhibidores de Topoisomerasa I , Trasplante Heterólogo , Células Tumorales Cultivadas/efectos de los fármacos , Agua/químicaRESUMEN
A 30-year-old female experienced a sudden sharp pain radiating down to the left leg from the lower back at epidural intubation for anesthesia at childbirth. She continued to complain of pain in the left leg afterwards. Magnetic resonance images demonstrated a conglomeration of adherent nerve roots due to lumbar adhesive arachnoiditis. Microsurgical dissection of adherent nerve roots was performed. Her symptoms disappeared after surgery, but soon recurred, being less severe and responsive to anti-inflammatory agents. Lumbar adhesive arachnoiditis should be considered for differential diagnosis in patients presenting with back and leg pain syndrome.
Asunto(s)
Anestesia Epidural , Anestesia Obstétrica , Aracnoiditis/etiología , Trastornos Puerperales/etiología , Adulto , Aracnoiditis/patología , Aracnoiditis/cirugía , Diagnóstico por Imagen , Femenino , Humanos , Examen Neurológico , Embarazo , Trastornos Puerperales/patología , Trastornos Puerperales/cirugía , Recurrencia , Raíces Nerviosas Espinales/patología , Raíces Nerviosas Espinales/cirugía , Adherencias TisularesRESUMEN
Eleven novel hexacyclic and three 7,9-disubstituted pentacyclic derivatives of camptothecin were synthesized and evaluated for in vitro cytotoxic activity against P388, HOC-21, and QG-56 and in vivo antileukemic activity against P388 in mice. Hexacyclic compounds which have an additional 5-, 6-, or 7-membered ring cyclized at positions 7 and 9 of camptothecin were prepared by intramolecular cyclization of pentacyclic camptothecin derivatives or Friedländer condensation of the appropriate bicyclic amino ketone and tricyclic ketone. All of the hexacyclic compounds exhibited compatible or superior activity of 7-ethyl-10-hydroxycamptothecin (SN-38) in in vitro assays without regard to the size or type of the additional ring, and three of six compounds showed more than 300% T/C on in vivo assay. These results suggest that the potency of the hexacyclic ring system is higher than that of the original pentacyclic ring system of camptothecin and that the conformational rigidity of substituents at positions 7 and 9 is favorable for antitumor activity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Animales , Camptotecina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Leucemia P388/tratamiento farmacológico , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
We have attempted to investigate the usefulness of the subrenal capsule assay (SRCA). Initially, we compared the results of antitumor activities of 27 anticancer drugs obtained using the SRCA in BDF1 mice and the subcutaneous transplantation assay in nude mice, and it became clear that these results correlated well. It was thus apparent that the antitumor activity of drugs could be evaluated faster, more cheaply and more easily using the SRCA. In the SRCA, the overall success rate for growing tumors (with a tumor growth rate of more than 1.0) from patients was 79% (106/134) and the success rates for each tumor type were as follows: malignant lymphoma 90%, ovarian cancer 87%, sarcoma 77%, breast cancer 76%, colorectal cancer 73% and renal cancer 58%. In a retrospective analysis of correlation between the antitumor activities assayed by the SRCA and the respective clinical responses, 11 out of 25 trials were true positive (79%) and 7 trials were true negative (64%). The sensitivity and specificity levels of this test were 73% and 70%, respectively. The tumor growth inhibition rates were correlated well with the clinical responses. The advantages of the SRCA are: it has a high success rate; it allows rapid evaluation; it can be applied for masked compounds; and it has a good clinical correlation. These advantages indicate that the SRCA is of potential value as a predictive test for selection of anticancer drugs on an individual patient basis.
Asunto(s)
Antineoplásicos/farmacología , Ensayo de Unidades Formadoras de Colonias , Evaluación Preclínica de Medicamentos/métodos , Ensayo de Tumor de Célula Madre , Animales , Ciclofosfamida/farmacología , Ciclosporinas/farmacología , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Ribonucleósidos/farmacologíaRESUMEN
Enhancements of cytotoxic effects of adriamycin (ADM) and vincristine (VCR) on PC-6 (lung cancer cell line) and Hattori (breast cancer cell line) were investigated by concomitant use of a calmodulin inhibitor: nicardipine, antiplatelet agents: oxyfedrine and trimethazidine and an antihypertensive agent: trichlormethiazide. Nicardipine increased the cytotoxic activity of both drugs but other agents did not produce any significant increase. Nicardipine increased the cytocidal effect of VCR on PC-6 about 2-fold and on Hattori about 3-fold. Furthermore, it also increased the effect of ADM on Hattori about 2-fold. Thus, nicardipine enhanced the cytocidal activity of VCR more remarkably than that of ADM.