Sweet P, Chan P K, Slater L M
Department of Medicine, California College of Medicine, University of California, Irvine 92717.
Cancer Res. 1989 Feb 1;49(3):677-80.
It has recently been shown that anthracycline antibiotic-resistant tumor cells are less responsive to daunorubicin-stimulated B23 nucleolar phosphoprotein translocation than drug-sensitive cells. Since cyclosporin A and verapamil reverse primary acquired and secondary cross-resistance to daunorubicin, we investigated the effect of these agents on nucleolar B23 translocation in sensitive and resistant tumors. We compared modified to baseline B23 phosphoprotein distribution between predominantly nucleolar, mixed nucleolar-nuclear, or nuclear immunofluorescence using a monoclonal anti-B23 antibody in parental drug-sensitive and multidrug-resistant acute lymphatic leukemia and in daunorubicin-sensitive and -resistant murine hepatoma. Our experiments show that cyclosporin A and verapamil alone have no effect on B23 phosphoprotein translocation, but that the addition of either agent to sensitive parental or resistant tumor sublines markedly enhances daunorubicin-stimulated translocation. This effect correlates with the correction of impaired daunorubicin inhibition of RNA synthesis by cyclosporin A and verapamil in the resistant sublines. Our observations suggest that nucleolar B23 phosphoprotein is an important site in the modulation of anthracycline antibiotic antitumor activity.
最近研究表明，与药物敏感细胞相比，蒽环类抗生素耐药肿瘤细胞对柔红霉素刺激的B23核仁磷蛋白易位反应较弱。由于环孢素A和维拉帕米可逆转对柔红霉素的原发性获得性耐药和继发性交叉耐药，我们研究了这些药物对敏感和耐药肿瘤中核仁B23易位的影响。我们使用单克隆抗B23抗体，比较了亲代药物敏感和多药耐药急性淋巴细胞白血病以及柔红霉素敏感和耐药小鼠肝癌中，主要为核仁、核仁-核混合或核免疫荧光之间B23磷蛋白分布相对于基线的变化。我们的实验表明，单独使用环孢素A和维拉帕米对B23磷蛋白易位没有影响，但将这两种药物中的任何一种添加到敏感亲代或耐药肿瘤亚系中，均可显著增强柔红霉素刺激的易位。这种效应与环孢素A和维拉帕米纠正耐药亚系中柔红霉素对RNA合成抑制受损有关。我们的观察结果表明，核仁B23磷蛋白是调节蒽环类抗生素抗肿瘤活性的重要位点。
