Circumvention of resistance to daunorubicin by N-acetyldaunorubicin in Ehrlich ascites tumor.
Circumvention of resistance to daunorubicin by N-acetyldaunorubicin in Ehrlich ascites tumor.
复制标题
N-乙酰柔红霉素在艾利希腹水瘤中规避柔红霉素耐药性。
作者：
T. Skovsgaard
实验证据表明，对柔红霉素（DNR）有抗性的艾利希腹水肿瘤细胞比野生型细胞具有更高的活性药物排出量。在本研究中，我们在体外和体内研究了通过添加 DNR 类似物 N-乙酰柔红霉素 (N-乙酰-DNR) 来规避这种耐药机制的可能性。在野生型和耐药细胞的裂解物中，N-乙酰基-DNR 的亲和力比 DNR 低 7 倍。与这一发现一致，N-乙酰基-DNR 仅在较小程度上减少了 [3H]DNR 与两种细胞系裂解物的结合。另一方面，N-乙酰基-DNR 对两种细胞系中[3H]DNR 的主动流出和单向流入均具有显着抑制作用。在一定限度内，添加 N-乙酰基-DNR 会导致 [3H]DNR 的稳态摄取增加；在野生型细胞中，最大可获得的升高为 18%，而耐药细胞中为 142%。体内添加 N-乙酰基-DNR，即使连续 4 天 80 mg/kg，也不会影响 DNR 对小鼠的毒性。在治疗实验中，添加N-乙酰基-DNR显着增加了DNR对耐药肿瘤系的抗肿瘤活性，但在野生型肿瘤中没有观察到变化。这些数据表明N-乙酰基-DNR或相关类似物可用作佐剂来规避对DNR的获得性抗性。
Experimental evidence indicates that Ehrlich ascites tumor cells resistant to daunorubicin (DNR) have a higher active drug extrusion than do wild-type cells. In the present study, the possibility of circumventing this mechanism of resistance by addition of an analog of DNR, N-acetyldaunorubicin (N-acetyl-DNR), was investigated in vitro and in vivo. The affinity of N-acetyl-DNR was 7 times lower than that of DNR in the lysates of both wild-type and resistant cells. In agreement with this finding, N-acetyl-DNR reduced the binding of [3H]DNR to lysate from the two cell lines only to a minor extent. On the other hand, N-acetyl-DNR exerted a marked inhibition on both the active efflux and the unidirectional influx of [3H]DNR in both cell lines. Within certain limits, addition of N-acetyl-DNR resulted in increased steady-state uptake of [3H]DNR; in wildtype cells, the maximal obtainable elevation was 18%, compared to 142% in resistant cells. In vivo addition of N-acetyl-DNR, even at 80 mg/kg for 4 consecutive days, did not influence the toxicity of DNR in mice. In a therapeutic experiment, addition of N-acetyl-DNR increased the antitumor activity of DNR upon the resistant tumor line significantly, but no change was observed in the wild-type tumor. These data indicate that N-acetyl-DNR or related analogs may be used as adjuvants to circumvent acquired resistance to DNR.