Modification of Anti-cancer Drug Formula and Its Local Administration

目前的临床肿瘤化疗除对部分泌尿生殖道和淋巴道肿瘤外，效果并不理想。如何提高现有抗癌药物的疗效已成为目前研究的热点问题之一。从这一观点出发，已经进行了许多尝试，例如药物的结构修饰、给药途径或剂量方案的改变以及特定药物递送系统的开发，以改善药剂的化学治疗性质。目前的研究致力于开发定时释放系统，其可以在所需的时间段内为肿瘤部位提供足够量的抗癌剂，并致力于这些药物的局部给药。为此目的，已经开发和研究了结构修饰的药物，如脂肪乳剂和MMC-葡聚糖缀合物。在使用家兔的实验研究中，使用油包球型（S/O）乳剂极大地提高了博莱霉素转移到淋巴结中的速率及其从淋巴结持续释放的速率--比使用W/O乳剂高两倍以上。临床上，34例淋巴管瘤和14例晚期胃肠道肿瘤采用脂肪（S/O）乳剂（BET）局部给药。结果令人满意，表明BET比手术治疗淋巴管瘤更有益。本文研究了丝裂霉素C的高分子量前药--丝裂霉素-葡聚糖偶联物（MMC-D）的抗肿瘤活性，其瘤内注射对实验性肿瘤的作用上级丝裂霉素。另一项实验研究表明，MMC-D的抗肿瘤作用受电荷和分子量的控制。瘤内注射MMC-D治疗晚期不能手术的胃肠道癌13例中有6例（47%）有临床疗效。

Results of current clinical cancer chemotherapy have been not satisfactory good except for ones against a part of urogenital and lymphatic tumors. It has been one of the most important problems how the effect of anticancer agents currently available can be enhanced. From this view point, numerous attempt such as structural modification of the drug, alteration in route of administration or dose regimen, and development of a specific drug delivery system have been made to improve chemotherapeutic properties of agents. The effort in the current study has been directed towards the development of timed-release systems, which could provide the tumor site with sufficient amount of anticancer agents for required period of time, and towards topical administration of those drugs. The structurally modified drugs such as a fat emulsion and MMC-Dextran conjugate have been developed and studied for this purpose. Tn the experimental study using domestic rabbits the rate of transfer of bleomycin into lymph nodes and of its sustained release from the nodes was extremely enhanced by the use of a sphere-in-oil type (S/O) emulsion -- more than two times higher than in the use of a W/0 emulsion. Clinically, 34 cases with lymphangiomas and 14 cases with advanced gastrointestinal cancers were treated by topical administration of drugs intratumorally in a fat (S/O) emulsion (BET). Results were satisfactory, indicating BETs would be more beneficial than surgical treatments for lymphangiomas. The antitumor activity of a high molecular weight pro-drug of mitomycin C, MMC-dextran conjugate (MMC-D), was examined and its intratumoral injection showed a superior effect on experimental tumors compared with MMC. Another experimental study has demonstrated that the antitumor effect of MMC-D is governed by electric charge and molecular weight. Clinical effects of the treatment by intratumoral injection of MMC-D were found in 6 of 13 patients (47 %) with advanced inoperable gastrointestinal cancer.