ANTITUMOR ACTIVE ETHER PHOSPHOLIPIDS

化疗仍然在控制癌症中发挥着关键作用。 肿瘤性疾病 开发具有强效的化学制剂 和选择性抗癌活性尤其有希望 用于治疗那些恶性肿瘤（如白血病）， 其他干预措施无效或不切实际。 之一 这一领域最令人兴奋的新发展是 发现了一组合成的醚磷脂， 有效地直接和选择性地破坏细胞， 许多人白血病和实体瘤在体外，一些 同种异体和同基因小鼠肿瘤体内生长，以及 抑制Lewis肺癌转移的发展 在同基因小鼠中。 此外，I期临床研究报告称， 在实体瘤患者中记录良好的客观缓解， 包括支气管癌和急性髓性白血病。 由于治疗水平被发现是无毒的正常 细胞，有人建议，使用合成醚 磷脂可以为人类肿瘤提供一种新的方法 疗法 高效选择性醚化磷脂的研制 肿瘤细胞毒性是该研究项目的主要目标。 我们将设计结构修饰的磷脂化合物， 根据实验确定的要求开发 用于抗肿瘤效力和选择性。 合成将是 使用我们最近开发的方法完成 实验室 这些合成化合物将在多个 合作研究。 将测定效价和选择性 3H-胸苷摄取和胞质LDH释放后， 通过计数正常与癌源的活细胞。 免疫学测试将评估巨噬细胞活化的程度 和单核细胞分化诱导。 14C-血清素释放将 用于测量血小板活化、自发性高血压 将使用大鼠测定抗高血压活性。

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.