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.
D000666:Amphotericin B / Q000008:administration & dosage*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004357:Drug Synergism; D004806:Ependymoma / Q000188:drug therapy*; D008130:Lomustine / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009607:Nitrosourea Compounds / Q000008:administration & dosage*; D012334:RNA, Neoplasm / Q000096:biosynthesis*
D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D012334:RNA, Neoplasm; D008130:Lomustine; D000666:Amphotericin B