Maksymowych A B, Robertson N M, Litwack G
Department of Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Anticancer Res. 1993 Nov-Dec;13(6A):1925-37.
We have demonstrated, using confocal laser scanning microscopy, that pyridoxal treatment of B16C3 murine melanoma cells inhibits triamcinolone acetonide induced translocation of the glucocorticoid receptor to the nucleus of intact cells. In addition to inhibiting glucocorticoid receptor nuclear translocation, pyridoxal kills B16C3 murine melanoma cells and WM983A human melanoma cells in culture. Cortexolone, a glucocorticoid antagonist, also kills cells in culture. This mechanism, however, appears to initiate in the glucocorticoid receptor signal transducing cascade at a point prior to the impact of pyridoxal treatment alone. The glucocorticoid antagonist RU486 has no detrimental effect on melanoma cell viability, however, in combination with pyridoxal, RU486 extends cell viability. Since pyridoxal kills melanoma cells in culture, a pilot study was carried out examining the efficacy of topical application of a pyridoxal cream to inhibit the growth and/or cause regression of (B16C3) xenograft melanoma tumors in an immunocompetent (Hairless Rhino-J3) and an immunocompromised (Crl: nu/nu (CD1)BR) murine animal model. The results of the study with immunocompetent animals are encouraging. While tumors are brought under control by pyridoxal treatment, further work is needed to determine the most efficacious treatment regimen and to establish formal concentrations for pyridoxal in topical ointments. Trials using immunocompromised animals indicated that although some qualitative differences may be detected between the control and experimental animals, tumor growth in these animals is so aggressive that multiple applications or higher concentrations of pyridoxal may be needed to obtain useful data.
我们利用共聚焦激光扫描显微镜证明，用吡哆醛处理B16C3小鼠黑色素瘤细胞可抑制曲安奈德诱导的糖皮质激素受体向完整细胞的细胞核转位。除了抑制糖皮质激素受体的核转位外，吡哆醛还能在培养中杀死B16C3小鼠黑色素瘤细胞和WM983A人黑色素瘤细胞。皮质酮，一种糖皮质激素拮抗剂，也能在培养中杀死细胞。然而，这种机制似乎在糖皮质激素受体信号转导级联反应中，在单独使用吡哆醛处理之前的某个点就开始了。糖皮质激素拮抗剂RU486对黑色素瘤细胞活力没有有害影响，然而，与吡哆醛联合使用时，RU486可延长细胞活力。由于吡哆醛能在培养中杀死黑色素瘤细胞，因此进行了一项初步研究，考察局部应用吡哆醛乳膏在免疫健全（无毛犀牛-J3）和免疫受损（Crl:nu/nu(CD1)BR）小鼠动物模型中抑制（B16C3）异种移植黑色素瘤肿瘤生长和/或使其消退的疗效。免疫健全动物的研究结果令人鼓舞。虽然吡哆醛处理可控制肿瘤，但还需要进一步的工作来确定最有效的治疗方案，并确定局部软膏中吡哆醛的正式浓度。使用免疫受损动物的试验表明，尽管在对照动物和实验动物之间可能检测到一些定性差异，但这些动物的肿瘤生长非常迅速，可能需要多次应用或更高浓度的吡哆醛才能获得有用的数据。
