Inhibition of RNA synthesis in murine ependymoblastoma by the combination of amphotericin B and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

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.

Lipid composition of plasma membranes from human leukemic lymphocytes.

The specific activity of adenosine 5'-monophosphatase and the concentrations of cholesterol, glucosylceramide, lactosylceramide, and phospholipids were compared in the whole homogenates and in plasma membrane fractions in four preparations of human leukemic lymphocytes taken over a 1-yr period from a patient with chronic lymphocytic leukemia. There was a 69.5-fold enrichment of the specific activity of adenosine 5'-monophosphatase in plasma membrane fractions. This enzyme appeared to be the best plasma membrane marker of all compounds studied. The increase in lactosylceramide concentration in the plasma membranes was 34.4-fold. It was significantly higher than that of glucosylceramide. The enrichment of glucosylceramide in the plasma membranes was similar to that of cholesterol and total phospholipids. The pattern of individual phospholipids in the plasma membrane fraction, as compared with the whole homogenate, was characterized by a decrease in phosphatidylcholine and an increase in sphingomyelin.

Variations of homovanillic acid levels in ventricular cerebrospinal fluid.

We studied the nycterohemeral variations of homovanillic acid (HVA) in ventricular cerebrospinal fluid (CSF) in 24 patients undergoing monitoring of intracranial pressure as part of the normotensive hydrocephalus (NTH) work-up. CSF samples were obtained every 4 h in each patient. The mean individual values of HVA in the ventricular CSF ranged from 133 to 421 ng/ml, and they could not be correlated to any clinical feature. The intraindividual levels of HVA were stable throughout 24 hours, with a variation coefficient inferior to 10% in 63% of cases, and inferior to 20% in all the patients.