Development of efficient production of antitumor agents originated from plant and their application to antitumor therapy using hybrid liposomes

研究了紫杉醇（Taxol）等抗肿瘤药物有效产生的培养条件和愈伤组织培养中愈伤组织生长的改善情况（见下文1-3）。为了增强紫杉醇对肿瘤细胞生长的抑制作用，我们制备了包括生物材料和紫杉醇的杂交脂质体，并考察了它们的生长抑制作用（见下文4）。得到的结果如下：1。由于紫杉醇的疏水相互作用，从多种有机溶剂中选择合适的易溶解紫杉醇的有机溶剂从水介质中回收紫杉醇。对数P值大于5的脂肪烃、脂肪醇和甘油三酯是提高紫杉醇产量和促进愈伤组织生长的良好候选物质。在选定的有机溶剂中溶解的诱导子对紫杉醇的产生和愈伤组织的生长是有效的。用具有明显疏水性的泡沫代替有机溶剂从介质中回收紫杉醇。在愈伤组织培养中观察到泡沫中紫杉醇的选择性积累，这表明泡沫是紫杉醇选择性恢复的良好候选物。对于愈伤组织的大规模培养，一般采用搅拌式或泡柱式生物反应器。研究了不同摇动速度对愈伤组织生长和紫杉醇产量的影响。研究了维持愈伤组织生长和紫杉醇产量的最佳摇动速度。利用生物材料提高紫杉醇在水中的溶解度。含有生物材料和紫杉醇的杂化脂质体同时形成合适大小的脂质体，并稳定数周。此外，杂交脂质体对肿瘤细胞的生长有抑制作用。这些数据表明，这种混合脂质体可能是一种治疗癌症的新型化疗药物。

Culture conditions for the effective production of antitumor agents such as Paclitaxel (Taxol) and improvement of callus growth in the callus culture were examined (refer to 1-3 below). To enhance the inhibitory effect of Taxol on the growth of tumor cells, hybrid liposomes including biological materials and Taxol were prepared and their growth inhibitory effects were also examined (refer to 4 below). The results obtained are as follows.1. Appropriate organic solvents, which solubilized Taxol easily, were selected from a variety of organic solvents to recover Taxol from the aqueous medium due to hydrophobic interaction. Aliphatic hydrocarbons having log P values of more than 5, fatty alcohols and triglycerides were good candidates for the enhancement of Taxol production and improvement of the callus growth. An elicitor solubilized in selected organic solvents was effective for the Taxol production and the callus growth.2. Foam, which has an apparently hydrophobic property, was used for the recovery of Taxol from the medium instead of the organic solvents. Selective accumulation of Taxol in the foam was observed in the callus culture, which indicated that foam had an excellent candidate for selective recovery of Taxol.3. Generally, stirred or bubble column bioreactor was utilized for the large scale callus culture. The effect of shaking speeds on the callus growth and Taxol production was examined. Optimum shaking speed for maintaining callus growth and Taxol production was examined.4. Biological materials were used to increase the solubility of Taxol in water. Hybrid liposomes including biological materials and Taxol simultaneously formed appropriate size of liposomes and were stable for several weeks. Besides, the hybrid liposomes showed an inhibitory effect on the growth of the tumor cells. The data suggest that the hybrid liposomes could be a novel chemotherapeutic agent in the treatment of cancers.