Laurent G, Dewerie-Vanhouche J, Machin D, Hildebrand J
Cancer Res. 1980 Mar;40(3):939-42.
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.
本研究的目的是阐明两性霉素B（AMB）增强1-(2-氯乙基)-3-环己基-1-亚硝基脲（CCNU）对小鼠皮下室管膜母细胞瘤抗肿瘤作用的机制。研究了AMB对肿瘤细胞对环己基部分标记的CCNU通透性的影响。每只小鼠肌内注射10.4微居里的1-(2-氯乙基)-3-[环己基-1-14C]环己基-1-亚硝基脲后1、6、14和25小时，在接受AMB（在[14C]CCNU注射前10小时给予25mg/kg）治疗的动物肿瘤中测得的放射性显著高于对照组（p<0.001）。分别或联合给予AMB和CCNU对RNA和蛋白质合成的影响，分别通过测量[3H]尿苷和[14C]亮氨酸掺入RNA和蛋白质来研究。每只小鼠腹腔注射40微居里标记前体2小时后，给予AMB（25mg/kg）或CCNU（10mg/kg）不影响[3H]尿苷的掺入。另一方面，与单独接受CCNU的动物相比，先给予AMB（25mg/kg）10小时后再给予CCNU（10mg/kg）的动物中，[3H]尿苷的掺入受到显著抑制（p<0.001）。CCNU给药后24小时，抑制作用最大可达约35%，而在CCNU之后给予AMB时未观察到这种抑制作用。在用AMB和CCNU的降解产物环己基异氰酸酯（5.4mg/kg）治疗的小鼠中也观察到了RNA合成的抑制。[14C]亮氨酸掺入的测量结果表明，AMB不会增加CCNU对蛋白质合成的抑制作用。这些观察结果表明，AMB增加了CCNU降解产生的环己基衍生物的摄取。这种化合物摄取的增加导致RNA合成的抑制。至少在小鼠室管膜母细胞瘤中，这种机制可以解释AMB对CCNU治疗效果的增强作用。
