Basic and Clinical Research for Treatment of Malignant Ovarian Tumor

卵巢癌的晚期和耐药性给治疗带来了许多困难。我们组织了东海卵巢肿瘤研究组，登记的患者随机接受CAP（环磷酰胺、阿霉素、顺铂）或PVB（顺铂、长春碱、博莱霉素）治疗。181例中47例临床症状无缓解，86%的患者在初次手术后20个月内死亡。54例无复发和随后复发。多因素分析的独立缓解因素是较高的分期、透明细胞癌、较大的最大残留肿瘤和PVB治疗。使用PVB治疗获得了显著高的缓解率和低复发率。临床缓解后的无病生存率与二次剖腹探查阴性后的无病生存率相同，这意味着在卵巢癌的治疗中可能不需要二次剖腹探查。在第二次手术和第一次手术中，与未行淋巴结清扫的患者相比，完全切除肿瘤并行淋巴结清扫的患者的无病生存率更高。目前正在进行一项比较CAP和PP（顺铂、卡铂）的随机试验，并提出了几种可能的顺铂耐药机制。与来源于卵巢浆液性囊腺癌的亲本细胞（NOS 2）相比，NOS 2CR细胞显示出7.0倍的顺铂抗性。NOS 2 CR细胞内顺铂含量降低和GST活性升高是其主要机制。两性霉素B（AMB）可增强阿霉素、丝裂霉素C等抗癌药物的细胞毒作用。AMB使NOS2CR和NOS2对顺铂敏感，部分原因是顺铂的细胞内积累增加。此外，与顺铂单独给药相比，AMB和顺铂腹腔内给药可增加荷瘤裸鼠的生存时间。

Ovarian carcinoma presents many difficulties in treatment because of the advanced stage and drug resistance. We organized Tokai ovarian tumor study group and registered patients were treated with CAP (cyclophosphamide, adriamycin, cisplatin) or PVB (cisplatin, vinblastin, bleomycin) randomly. Forty-seven of 181 cases had no clinical remission and 86% of them died within 20 months after primary surgery. Fifty-four cases had no recurrence and a subsequent recurrence. Independent remission factors by multivariate analysis were higher stage, clear cell carcinoma, larger maximum residual tumor, and PVB therapy. A significantly high remission rate and low recurrence rate was achieved using PVB therapy. The disease-free survival after clinical remission was the same as that after a negative second-look laparotomy, which implies that a second-look laparotomy may be unnecessary in the management of ovarian carcinoma. Complete resection of tumor with lymphadnectomy tended to increase disease-free survival compared to that without lymphadnectomy in the second operation as well as the first. Now, a randomized trial comparing CAP or PP (cisplatin, carboplatin) is under way.Several possive mechanism of the resistance to cisplatin are proposed. NOS2CR cells show 7.0 times resistance to cisplatin compared to parental cells (NOS2) derived from serous cystadenocarcinoma of the ovary. Decreased intracellular cisplatin content and increased activity of GST are the main mechanisms in NOS2CR.Amphotericin B (AMB) can potentiate the cytotoxicity of anticancerdrugs, such as adriamycin and mitomycin C.The enhancing effect of AMB on cisplatin was examined. AMB sensitized NOS2CR as well as NOS2 to cisplatin, partially due to the increasing intracellular accumulation of cisplatin. Furthermore, intraperitoneal administration of AMB and cisplatin produced an increase in survival time in tumor-bearing nude mice compared to cisplatin alone.