ANTITUMOR ACTIVE ETHER PHOSPHOLIPIDS

化疗在控制艾滋病方面继续发挥着关键作用。 肿瘤疾病。强效化学制剂的发展 而选择性抗癌活性尤其有希望 用于治疗那些恶性疾病(如白血病) 替代干预措施要么无效，要么不切实际。其中之一 这一领域最令人兴奋的新发展是 发现了一组合成醚磷脂 有效地直接和选择性地摧毁来自 大量的人类白血病和实体瘤在体外，一些 同种异体和同基因小鼠体内肿瘤生长，以及 抑制Lewis肺癌转移的实验研究 在同基因小鼠身上。此外，第一阶段临床研究报告 实体瘤患者的客观反应得到了很好的证明， 包括肺癌和急性髓系白血病。 因为治疗水平被发现对正常无毒 细胞，有人建议使用合成醚 磷脂可能成为治疗人类肿瘤的新途径 心理治疗。 高效选择性乙醚磷脂的研究进展 肿瘤细胞毒性是本研究项目的主要目的。 我们将设计结构修饰的磷脂化合物，将 根据实验确定的要求进行开发 具有抗肿瘤效力和选择性。综合将是 使用最近在我们的 实验室。这些合成化合物将在多个 合作研究。效力和选择性将被确定 在~3H-胸腺嘧啶核苷摄取和胞浆乳酸脱氢酶释放后，以及 通过对正常来源和癌症来源的活细胞进行计数。 免疫学测试将评估巨噬细胞激活的程度 诱导单核细胞分化。14C-5-羟色胺释放将 用于测量自发性高血压患者的血小板活化程度 大鼠将被用来确定抗高血压活性。

Chemotherapy continues to play a key role in the control of neoplastic diseases. Development of chemical agents with potent and selective anticancer activity holds the promise particularly for the treatment of those malignancies (such as leukemia) where alternative interventions are ineffective or impractical. One of the most exciting new developments in this area has been the discovery that a group of synthetic ether phospholipids were shown effective in directly and selectively destroying cells from numerous human leukemias and solid tumors in vitro, a number of allogeneic and syngeneic mouse tumor-growths in vivo, and in inhibiting the development of metastases of lewis lung carcinoma in syngeneic mice. Furthermore, phase I clinical studies reported well-documented objective response in patients with solid tumors, including bronchogeneic carcinomas and with acute myeloid leukemia. As the therapeutic levels were found to be nontoxic to normal cells, it was suggested that the use of synthetic ether phospholipids could present a new approach to human neoplastic therapy. Development of ether phospholipids with highly potent and selective tumor cytotoxicity is the main objective of this research project. We will design structural modified phospholipid compounds that will be developed on the basis of experimentally determined requirements for antitumor potency and selectivity. The synthesis will be accomplished using the methods recently developed in our laboratory. The synthetic compounds will be tested in a number of collaborative studies. Potency and selectivity will be determined following 3H-thymidine uptake and the release of cytosolic LDH, and by enumeration of viable cells of normal vs. cancerous origin. Immunological tests will assess the extent of macrophage activation and monocyte differentiation induction. 14C-serotonin release will be used to measure platelet activation, spontaneous hypertensive rats will be used to determine antihypertensive activity.