Shikani A H, Domb A J
Division of Otolaryngology--Head and Neck Surgery, The Good Samaritan Hospital, Baltimore, Maryland 21239, USA.
Laryngoscope. 2000 Jun;110(6):907-17. doi: 10.1097/00005537-200006000-00004.
To study a new method of delivery of chemotherapy for the treatment of squamous cell carcinomas (SCCs) of the head and neck, to evaluate the pharmacokinetics of four anticancer agents (cisplatin, fluorouracil [5-FU], methotrexate [MTX], and paclitaxel) loaded into the biodegradable polymer, polyanhydride polymer poly(FAD:SA), and to evaluate the effectiveness and toxicity of the drug-polymer combination against human SCCs, both in vitro and in vivo.
Poly(FAD:SA) was loaded with different chemotherapeutic drugs and its in vitro and in vivo drug release and tissue penetration characteristics were studied. The biocompatibility and toxicity of the polymer-drug combination were determined. The effectiveness of the drug-polymer was evaluated against three different human SCCs (larynx O11, pharynx FADU, and floor of mouth UM- SCC1) cultured in vitro and in nude mice carrying human SCC xenografts.
The in vitro drug release pharmacokinetics of the drugs were performed using atomic absorption spectrometry for cisplatin and high-pressure liquid chromatography for the 5-FU, MTX, and paclitaxel studies. In vitro tumor cytotoxicity was assessed by growth assay. In vivo cytotoxicity was assessed by growth rate inhibition in a nude mouse model.
All four chemotherapy drugs demonstrated a continuous release that followed first-order kinetics from the polymer. More than 95% of the MTX and 5-FU, 70% of the cisplatin, and 20% of the paclitaxel was released within the 10 days of the assay. Tumor cytotoxicity revealed that the polymer was very effective against the human SCCs O11, FADU, and UM- SCC1 in vitro. When a small amount of polymer (1-2 g) was added to the cell culture and left for 7 days, 96.6% of the UM-SCC1 cells, 86.9% of the FADU cells, and 94.6% of the O11 cells were killed. When the culture medium was then changed every 2 days to remove the effect of nutrient depletion or chemicals released by the degrading polymer, 74% of the UM-SCC1 cells, 94.5% of the FADU cells, and 66.1% of the O11 cells were killed at 7 days. The tumor animal model was the nude mouse carrying human floor of mouth SCC xenografts. Different amounts of cisplatin were incorporated into the polymers (5% and 7% drug/polymer at a weight/weight [wt/wt] load). Thirty-five days after implantation of the polymer in nude mice, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. The blank polymer was well tolerated by the mouse and had no effect on tumor growth.
The study results indicate that polymer chemotherapy is effective against a variety of SCCs of the head and neck, both in vitro and in vivo, and may become a useful therapeutic option for head and neck cancer.
研究一种用于治疗头颈部鳞状细胞癌（SCC）的新型化疗给药方法，评估负载于可生物降解聚合物聚酸酐聚合物聚（FAD:SA）中的四种抗癌药物（顺铂、氟尿嘧啶[5-FU]、甲氨蝶呤[MTX]和紫杉醇）的药代动力学，并评估该药物-聚合物组合在体外和体内对人SCC的有效性和毒性。
将不同化疗药物负载于聚（FAD:SA）中，研究其体外和体内药物释放及组织渗透特性。测定聚合物-药物组合的生物相容性和毒性。评估该药物-聚合物对三种不同人SCC（喉O11、咽FADU和口腔底UM-SCC1）在体外培养以及在携带人SCC异种移植瘤的裸鼠体内的有效性。
使用原子吸收光谱法测定顺铂的体外药物释放药代动力学，使用高压液相色谱法测定5-FU、MTX和紫杉醇的体外药物释放药代动力学。通过生长试验评估体外肿瘤细胞毒性。通过裸鼠模型中的生长速率抑制评估体内细胞毒性。
所有四种化疗药物均显示从聚合物中呈一级动力学的持续释放。在测定的10天内，超过95%的MTX和5-FU、70%的顺铂以及20%的紫杉醇被释放。肿瘤细胞毒性显示该聚合物在体外对人SCC O11、FADU和UM-SCC1非常有效。当向细胞培养物中加入少量聚合物（1-2 g）并放置7天时，96.6%的UM-SCC1细胞、86.9%的FADU细胞和94.6%的O11细胞被杀死。然后每2天更换一次培养基以消除营养耗尽或降解聚合物释放的化学物质的影响，在7天时74%的UM-SCC1细胞、94.5%的FADU细胞和66.1%的O11细胞被杀死。肿瘤动物模型为携带人口腔底SCC异种移植瘤的裸鼠。将不同量的顺铂掺入聚合物中（以重量/重量[wt/wt]负载，药物/聚合物分别为5%和7%）。在裸鼠中植入聚合物35天后，5%组中治疗后的平均肿瘤大小为对照组的65.5%，7%组中为31.8%。植入70天后，5%组中治疗后的平均肿瘤大小为对照组的41.4%，7%组中为38.1%，表明与对照组或腹腔注射顺铂相比，肿瘤生长有统计学意义的延迟。空白聚合物在小鼠中耐受性良好，对肿瘤生长无影响。
研究结果表明，聚合物化疗在体外和体内对多种头颈部SCC均有效，可能成为头颈部癌的一种有用治疗选择。
