EVALUATION OF CYTOTOXICITY OF ANSAMYCINS TO DEFINED CELL LINES

赫比霉素A和格尔达那霉素(分别为HA和GA)均为苯喹类化合物 据报道，安沙霉素类抗生素可以逆转这种转化 病毒转化的上皮细胞的表型。当这些特工 酪氨酸激酶的体外弱抑制剂，其添加的结果 对细胞的影响是细胞蛋白磷酸酪氨酸含量的延迟降低 以及某些酪氨酸激酶的活性。这件事的重点是 项目是检查这些药物对细胞系的细胞毒性。 来源于神经外胚层，并与那些具有 神经分泌功能。其次，我们的重点是确定是否有 观察到的细胞毒性是由于酪氨酸激酶抑制或其他原因， 机制尚未确定。 我们已经确定这两种药物对两种药物都有很强的细胞毒性。 原始的、未分化的神经外胚层来源的肿瘤和 神经分泌特性。这些肿瘤包括髓母细胞瘤， 神经上皮癌、结肠癌、黑色素瘤和前列腺癌。 更分化的神经外胚层来源的细胞，如神经母细胞瘤， 不受影响。许多其他细胞系，代表了 造血系统和成纤维细胞，在浓度上不敏感 受雇的工作人员。我们已经能够在活体内证明 这些药物的有效性也是如此。使用皮下无性系 小鼠-人异种移植模型，我们观察到肿瘤明显减少 皮下给药后的肿块。研究的肿瘤是 前列腺癌(激素不敏感)和神经上皮瘤。没有公开的 对寄主有一定的毒性。我们还证明了这些药物 对人类神经上皮瘤的原代外植体有细胞毒性，而不是 影响正常大鼠大脑皮质和小脑活性的实验研究 文化。在所有病例中观察到的毒性都需要暴露在 细胞给药的时间短至一小时。

Herbimycin A and geldanamycin (HA and GA, respectively) are benzoquinoid ansamycin antibiotics which have been reported to reverse the transformed phenotype of virus-transformed epithelial cells. While these agents are weak inhibitors of tyrosine kinases in vitro, a result of their addition to cells is delayed reduction in cellular protein phosphotyrosine content and in the activity of certain tyrosine kinases. The focus of this project is to examine these agents' cytotoxicity against cell lines derived from the neuroectoderm and against those cell lines with neurocrine features. Secondarily, our focus is to determine whether any observed cytotoxicity is due to tyrosine kinase inhibition or to another, as yet undefined, mechanism. We have determined that both drugs are very cytotoxic against both primitive, undifferentiated neuroectoderm-derived tumors and tumors with neurocrine properties. These tumors include medulloblastomas, neuroepitheliomas, colon carcinomas, melanomas, and prostatic carcinomas. More differentiated neuroectoderm-derived cells such as neuroblastoma, are not affected. Many other cell lines, representative of the hematopoietic system and fibroblasts, are not sensitive at the concen- trations employed. We have been able to demonstrate in vivo effectiveness of these drugs as well. Using a subcutaneous athymic mouse-human xenograft model, we observed a significant reduction in tumor mass following subcutaneous drug administration. Tumors studied were prostatic carcinoma (hormone-refractory) and neuroepithelioma. No overt toxicity to the host was seen. We have also demonstrated that these drugs are cytotoxic to a primary explant of a human neuroepithelioma, while not affecting the viability of normal rat brain cortical and cerebellar cultures. The toxicities observed in all cases require an exposure of cells to drug of as little as one hour.