Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors.
Experimental studies and preliminary clinical trial of vinorelbine-loaded polymeric bioresorbable implants for the local treatment of solid tumors.
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发表时间：
1991-10
期刊：
影响因子：
11.2
通讯作者：
C. Fournier;B. Hecquet;P. Bouffard;M. Vert;A. Caty;M. Vilain;L. Vanseymortier;S. Merle;A. Krikorian;J. Lefebvre
中科院分区：
文献类型：
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作者：
C. Fournier;B. Hecquet;P. Bouffard;M. Vert;A. Caty;M. Vilain;L. Vanseymortier;S. Merle;A. Krikorian;J. Lefebvre
长春瑞滨是一种新的5‘-去甲长春花碱，具有静脉注射活性。治疗各种癌症疾病，如非小细胞肺癌和晚期乳腺癌。为了评价长春瑞滨用于肿瘤局部治疗的可能性，用D，L-乳酸和乙醇酸的共聚物(PLA37.5GA25)制备了长春瑞滨生物可吸收聚合物植入物。根据制备工艺，获得的直径1.2 mm的圆柱形棒体的药物含量分别为1、5或20%(w/w)，并在体外约6天内释放一半内容物。在大鼠体内的释放较慢，大约14天后药物释放了一半。当植入物被注入肿瘤内或与肿瘤接触时，在小鼠(实体P388白血病模型)中观察到了剂量依赖的抗肿瘤效应。在药物负荷最高时，当肿瘤植入后不久给药时，长春瑞滨植入剂比静脉注射更有效。给药(与未处理的对照相比，处理的动物的中位存活时间大于360，而未处理的对照为188)。在狗身上，毒性实验结果显示，必须避免在重要器官植入植入物。相反，S.C.对政府的容忍程度很高。植入后数天出现一过性局部坏死，约10周后恢复正常皮肤。因此，对头颈部癌症患者进行了临床试验；9名患者中有8名患者成功地将20%负载的聚合物植入物植入肿瘤部位。鞋底的失败归因于肿瘤组织的异常硬度。除了局部的一过性炎症反应(很容易用非类固醇抗炎药治疗)外，没有检测到其他毒性迹象，患者对该设备的耐受性良好。植入后14天，患者接受了计划中的手术，植入物被修复。残留药物含量从24%到55%不等。在所有病例中，种植体周围都有一个清楚界定的坏死区，直径从0.5到3.5厘米不等。在最小的肿瘤中，在该区域内的正常组织中也观察到了坏死。这些结果引发了进一步的研究，以评估这种载药聚合物植入物。
Vinorelbine is a new 5' nor Vinca alkaloid, active by i.v. route, in various types of cancer disease such as non-small cell lung cancer and advanced breast cancer. In order to evaluate the possibility of using this drug for local treatment of cancer, Vinorelbine-loaded bioresorbable polymeric implants were prepared using a copolymer of D,L-lactic and glycolic acids (PLA 37.5 GA 25). According to the manufacturing process, the 1.2-mm-diameter cylindrical rods obtained had a drug content of 1, 5, or 20% (w/w) and released half of their content within about 6 days in vitro. In vivo release in rats was slower, half of the drug being released after about 14 days. A dose-dependent antitumoral effect was observed in mice (solid P388 leukemia model) when implants were administered into or in contact with the tumor. At highest drug loads and when administered soon after tumor implantation, Vinorelbine implants were more effective than i.v. administration (median survival time of treated animals related to untreated controls, greater than 360 versus 188). In dogs, results of toxicity experiments revealed that administration of implants in vital organs must be avoided. On the contrary, s.c. administration was well tolerated. A transient local necrosis was observed in the days following implantation, but normal skin was recovered after about 10 weeks. Thus, a clinical trial was conducted on patients with head and neck cancer; implantation of 20% loaded polymeric implants into the tumor sites succeeded in 8 of 9 patients. The sole failure was attributed to the unusual hardness of the tumor tissue. Except for a local transient inflammatory reaction (easily treated with nonsteroidal antiinflammatory agents), no other sign of toxicity was detected, and patients tolerated the device well. Fourteen days after implantation, patients underwent their planned surgery, and the implants were recovered. Residual drug content varied from 24 to 55%. In all cases, there was a clearly delimited necrotic area around the implant, ranging from 0.5 to 3.5 cm in diameter. In the smallest tumors, necrosis was also observed in the normal tissue inside this area. These results invite further studies to evaluate such drug-loaded polymeric implants.