amphotericin-b and Ependymoma

Disseminated coccidioidomycosis should be considered as a diagnostic possibility whenever a patient has visited or resides in an endemic coccidioidal area and has a history of fever, skin rash, persistent pulmonary symptoms, bone pain, headache, or confusion. Imaging of this multisystem disease, especially of the lung, bone, and central nervous system, shows various protean manifestations that can simulate many infectious entities. The radiographic, scintigraphic, computed tomographic, or sonographic findings of this disease may be helpful in diagnosis, prognosis, and treatment follow-up in patients with disseminated coccidioidomycosis.

Topics: Amphotericin B; Angiography; Cerebral Ventriculography; Coccidioidomycosis; Ependymoma; Humans; Hydrocephalus; Knee; Lung Diseases, Fungal; Meningitis; Myelography; Radionuclide Imaging; Tomography, X-Ray Computed

The aim of this study was to clarify the mechanism of the potentiation by amphotericin B (AMB) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) antineoplastic effects on s.c. murine ependymoblastoma. The effect of AMB on tumor cell permeability to CCNU labeled on the cyclohexyl moiety was studied. The radioactivity measured in ependymoblastoma 1, 6, 14, and 25 hr after i.m. injection of 10.4 microCi of 1-(2-chlorethyl)-3-[cyclohexyl-1-14C]cyclohexyl-1-nitrosourea per mouse was significantly higher (p less than 0.001) in the tumors of animals treated with AMB (25 mg/kg 10 hr prior to [14C]CCNU) as compared to controls. The effects of AMB and CCNU given separately or in combination on RNA and protein synthesis were studied by measuring the incorporation of [3H]uridine and [14C]leucine, respectively, into RNA and proteins. The administration of AMB (25 mg/kg) or CCNU (10 mg/kg) did not affect the incorporation of [3H]uridine measured 2 hr after the i.p. injection of 40 microCi of labeled precursor per mouse. On the other hand, the incorporation of [3H]uridine was significantly (p less than 0.001) inhibited in animals treated with AMB (25 mg/kg) followed 10 hr later by CCNU (10 mg/kg), as compared to animals receiving CCNU alone. The inhibition, which reached a maximum of about 35% 24 hr after the administration of CCNU, was not observed when AMB was given after CCNU. The inhibition of RNA synthesis was also observed in mice treated with AMB and cyclohexyl isocyanate (5.4 mg/kg), a degradation product of CCNU. Measurements of [14C]leucine incorporation showed that AMB did not increase the inhibition of protein synthesis produced by CCNU. These observations suggest that AMB increases the uptake of a cyclohexyl derivative arising from the degradation of CCNU. The increased uptake of this compound results in inhibition of RNA synthesis. This mechanism could account for the potentiation of the CCNU therapeutic effect produced by AMB, at least in murine ependymoblastoma.

Topics: Amphotericin B; Animals; Biological Transport; Drug Synergism; Ependymoma; Lomustine; Mice; Neoplasm Proteins; Neoplasms, Experimental; Nitrosourea Compounds; RNA, Neoplasm

A method for the isolation of plasma membranes from an experimental murine ependymoblastoma is described. In this procedure, 5'-nucleotidase was used as the plasma membrane marker, since cytochemical methods demonstrated that the enzyme was present on this subcellular structure only. The final plasma membrane preparation showed a 15-fold enrichment in 5'-nucleotidase activity and a 17-fold enrichment in the activity of phosphodiesterase I, another plasma membrane marker. The specific activity of beta-glucuronidase (lysosomal enzyme) was twice that of the whole homogenate, the specific activity of arylesterase (microsomal enzyme) was similar to that of the whole homogenate and succinate dehydrogenase (mitochondrial marker) was not detected. Electron microscopy of this fraction showed vesicles on which 5'-nucleotidase activity could be demonstrated. The subcellular distribution of [3H]amphotericin B per mg of protein was similar in the plasma membrane preparation and in the whole homogenate. It is concluded that, in ependymoblastoma, amphotericin B shows no selective affinity for the plasma membrane.

Topics: Amphotericin B; Animals; Binding Sites; Cell Fractionation; Cell Membrane; Centrifugation, Density Gradient; Ependymoma; Esterases; Glucuronidase; Mice; Microscopy, Electron; Neoplasms, Experimental; Nucleotidases; Succinate Dehydrogenase

This paper reports the potentiation of the therapeutic effect of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) by amphotericin B (AMB) in s.c. transplanted murine ependymoblastoma 01B111. The rate of 2-month cures was 6% when tumors were treated 10 to 12 days after transplantation by a single 6 i.m. injection of 2.5 mg of CCNU per kg and reached 15% with 10 mg of CCNU per kg. When 25 mg of AMB per kg were given i.p. 10 hr prior to CCNU, the respective figures increased to 18 and 58%, the differences being significant at 5 and 1%. A single dose of 25 mg of AMB per kg given alone did not affect tumor growth. Radioactivity per g of tumor was measured 30, 60, and 120 min after injection of [14C]CCNU in total tissue, chloroform:methanol (2:1, v/v) extract, and CCNU isolated by thin-layer chromatography. No difference was found between animals treated with 25 mg of AMB per kg and controls. The inhibition of DNA synthesis, measured 24 hr after the administration of CCNU and 2 hr after the injection of [3H]thymidine, was almost optimal with 5 mg of CCNU per kg. The inhibition caused by 1 mg of CCNU per kg was not enhanced by AMB. Thus, the potentiation of CCNU by AMB does not seem attributable to an increased permeability of the tumor to CCNU or to an enhancement of the inhibition of DNA synthesis, at least in murine ependymoblastoma.

Topics: Amphotericin B; Animals; Cell Division; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Synergism; Ependymoma; In Vitro Techniques; Lomustine; Male; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Nitrosourea Compounds; Thymidine; Time Factors