Basic and Clinical Research for Treatment of Malignant Ovarian Tumor

由于卵巢癌的晚期和耐药，给治疗带来了许多困难。我们组织Tokai卵巢肿瘤研究组，注册患者随机接受CAP（环磷酰胺、阿霉素、顺铂）或PVB（顺铂、长春花素、博来霉素）治疗。181例患者中47例无临床缓解，86%的患者术后20个月内死亡。54例无复发，随后复发。多因素分析的独立缓解因素为分期高、透明细胞癌、最大残余肿瘤较大和PVB治疗。PVB治疗有明显的高缓解率和低复发率。临床缓解后的无病生存期与阴性复诊剖腹手术后的无病生存期相同，这意味着复诊剖腹手术在卵巢癌的治疗中可能是不必要的。在第二次和第一次手术中，完全切除肿瘤并行淋巴清扫术比不行淋巴清扫术更倾向于提高无病生存率。现在，一项比较CAP或PP（顺铂、卡铂）的随机试验正在进行中。本文提出了几种顺铂耐药的积极机制。NOS2CR细胞对顺铂的耐药性是来源于卵巢浆液性囊腺癌的亲本细胞（NOS2）的7.0倍。细胞内顺铂含量降低和GST活性升高是NOS2CR的主要机制。两性霉素B （AMB）可增强阿霉素和丝裂霉素c等抗癌药物的细胞毒性，并对其对顺铂的增强作用进行了研究。AMB使NOS2CR和NOS2对顺铂敏感，部分原因是细胞内顺铂积累增加。此外，与单用顺铂相比，腹腔注射AMB和顺铂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.