INHIBITION OF RNA-SYNTHESIS IN MURINE EPENDYMOBLASTOMA BY THE COMBINATION OF AMPHOTERICIN-B AND 1-(2-CHLOROETHYL)-3-CYCLOHEXYL-1-NITROSOUREA

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (3) , 939-942
Abstract
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 was clarified. 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 h after i.m. injection of 10.4 .mu.Ci of 1-(2-chloroethyl)-3-[cyclohexyl-1-14C]cyclohexyl-1-nitrosourea/mouse was significantly higher (P < 0.001) in the tumors of animals treated with AMB (25 mg/kg 10 h 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 h after the i.p. injection of 40 .mu.Ci of labeled precursor/mouse. The incorporation of [3H]uridine was significantly (P < 0.001) inhibited in animals treated with AMB (25 mg/kg) followed 10 h later by CCNU (10 mg/kg), as compared to animals receiving CCNU alone. The inhibition, which reached a maximum of about 35% 24 h 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. AMB apparently 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.

This publication has 0 references indexed in Scilit: