Sampath Prakash, Rhines Laurence D, DiMeco Francesco, Tyler Betty M, Park Michael C, Brem Henry
Department of Clinical Neurosciences Program in Neurosurgery, Brown Medical School, Rhode Island Hospital, Providence, RI 02903, USA.
J Neurooncol. 2006 Oct;80(1):9-17. doi: 10.1007/s11060-006-9159-4. Epub 2006 Apr 25.
Docetaxel (Taxotere) is a hemisynthetic, anti-cancer compound with good preclinical and clinical activity in a variety of systemic neoplasms. We tested its activity against malignant gliomas using local delivery methods. Antitumor activity was assessed in vitro against human (U87 and U80 glioma) and rat brain-tumor (9L gliosarcoma and F98 glioma) cell lines. For in vivo evaluation, we incorporated docetaxel into a biodegradable polymer matrix, determined associated toxicity in the rat brain, and measured efficacy at extending survival in a rat model of malignant glioma. Also, we examined the combined local delivery of docetaxel with carmustine (BCNU) against the experimental intracranial glioma. Rats bearing intracranial 9L gliosarcomas were treated 5 days after tumor implantation with various polymers (placebo, 5% docetaxel, 3.8% BCNU, or 5% docetaxel and 3.8% BCNU combination). Animals receiving docetaxel polymers (n=15, median survival 39.1 days) had significantly improved survival over control animals (n=12, median survival 22.5 days, P=0.01). Similarly, animals receiving BCNU polymers (n=15, median survival 39.3 days, 13.3% long-term survivors) demonstrated an increase in survival compared to the controls (P=0.04). Animals receiving the combination polymers demonstrated a modest increase in survival compared to either chemotherapeutic agent alone (n=14, median survival 54.9 days, 28.6% long-term survivors) with markedly improved survival over controls (P=0.003). We conclude that locally delivered docetaxel shows promise as a novel anti-glioma therapy and that the combination of drug regimens via biodegradable polymers may be a great therapeutic benefit to patients with malignant glioma.
多西他赛（泰索帝）是一种半合成的抗癌化合物，在多种全身性肿瘤中具有良好的临床前和临床活性。我们使用局部给药方法测试了其对恶性胶质瘤的活性。在体外评估了其对人（U87和U80胶质瘤）和大鼠脑肿瘤（9L胶质肉瘤和F98胶质瘤）细胞系的抗肿瘤活性。为了进行体内评估，我们将多西他赛掺入可生物降解的聚合物基质中，测定其在大鼠脑中的相关毒性，并在恶性胶质瘤大鼠模型中测量其延长生存期的疗效。此外，我们研究了多西他赛与卡莫司汀（BCNU）联合局部给药对实验性颅内胶质瘤的作用。颅内接种9L胶质肉瘤的大鼠在肿瘤植入后5天用各种聚合物（安慰剂、5%多西他赛、3.8% BCNU或5%多西他赛与3.8% BCNU组合）进行治疗。接受多西他赛聚合物治疗的动物（n = 15，中位生存期39.1天）的生存期明显长于对照动物（n = 12，中位生存期22.5天，P = 0.01）。同样，接受BCNU聚合物治疗的动物（n = 15，中位生存期39.3天，13.3%长期存活）与对照组相比生存期有所延长（P = 0.04）。接受联合聚合物治疗的动物与单独使用任何一种化疗药物相比生存期有适度延长（n = 14，中位生存期54.9天，28.6%长期存活），与对照组相比生存期明显改善（P = 0.003）。我们得出结论，局部给药的多西他赛有望成为一种新型抗胶质瘤疗法，通过可生物降解聚合物联合用药方案可能对恶性胶质瘤患者有很大的治疗益处。
