Burris H A, Fields S, Peacock N
Hematology/Oncology Service Drug Development Program, Brooke Army Medical Center, Ft Sam Houston, TX, USA.
Semin Oncol. 1995 Dec;22(6 Suppl 13):35-40.
Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a hemisynthetic derivative from European yew that inhibits tubulin depolymerization and enhances the formation of microtubule bundle aggregates, causing cell death. Activity against a variety of tumor types has been reported. Single-agent chemotherapy is rarely curative; hence, combination regimens are the logical next step in the attempt to improve tumor reduction and prolong survival. In preclinical studies, docetaxel has shown synergism with vinorelbine (Navelbine; Burroughs Wellcome Company, Research Triangle Park, NC), etoposide, cyclophosphamide, 5-fluorouracil, and methotrexate against a variety of murine tumors; in each case, at least 60% of the maximum tolerated dose could be administered without additional toxicity. Similar studies indicated an overlap in dose-limiting toxicity for docetaxel with cisplatin or doxorubicin, whereas with vincristine at least 80% of the maximum tolerated dose could be administered without additional toxicity. A number of docetaxel combinations are currently undergoing clinical evaluation and preliminary results appear to be encouraging. In a phase I trial, the docetaxel/5-fluorouracil combination exhibited activity against refractory solid tumors; grade IV neutropenia was observed, but there was no increase in gastrointestinal toxicity. The docetaxel/doxorubicin combination demonstrated impressive antitumor activity as front-line therapy for metastatic breast cancer (response rate, 70%), with little evidence of mucositis and dose-limiting toxicity experienced by only a minority of patients. Among 12 heavily pretreated phase I patients, the docetaxel/cyclophosphamide combination produced two partial responses in patients with breast cancer; three patients had febrile neutropenia and two had grade II mucositis. The docetaxel/vinorelbine combination produced responses at all dose levels as front-line therapy for metastatic breast cancer; dose-limiting toxicity was experienced by two patients, but only when the vinorelbine dose was raised to 22.5 mg/m2. In phase II studies in non-small cell lung cancer, preliminary results have shown the docetaxel/cisplatin combination to have a promising level of activity and an acceptable toxicity profile. Future trials will continue to evaluate the role of docetaxel in combination and in sequential regimens, most particularly in metastatic breast cancer and non-small cell lung cancer.
多西他赛（泰索帝；法国罗纳普朗克乐安公司，安东尼）是一种从欧洲紫杉中提取的半合成衍生物，它能抑制微管蛋白解聚并增强微管束聚集体的形成，从而导致细胞死亡。据报道，它对多种肿瘤类型都有活性。单药化疗很少能治愈疾病；因此，联合用药方案是提高肿瘤缩小率和延长生存期的合理下一步尝试。在临床前研究中，多西他赛已显示出与长春瑞滨（诺维本；美国北卡罗来纳州研究三角园的百时美施贵宝公司）、依托泊苷、环磷酰胺、5-氟尿嘧啶和甲氨蝶呤联合使用对多种小鼠肿瘤具有协同作用；在每种情况下，至少可以给予最大耐受剂量的60%而不会产生额外毒性。类似的研究表明，多西他赛与顺铂或阿霉素的剂量限制性毒性存在重叠，而与长春新碱联合使用时，至少可以给予最大耐受剂量的80%而不会产生额外毒性。目前，多种多西他赛联合用药方案正在进行临床评估，初步结果似乎令人鼓舞。在一项I期试验中，多西他赛/5-氟尿嘧啶联合用药方案对难治性实体瘤显示出活性；观察到IV级中性粒细胞减少，但胃肠道毒性没有增加。多西他赛/阿霉素联合用药方案作为转移性乳腺癌的一线治疗方案显示出令人印象深刻的抗肿瘤活性（缓解率为70%），只有少数患者出现黏膜炎和剂量限制性毒性的迹象。在12例经过大量预处理的I期患者中，多西他赛/环磷酰胺联合用药方案在乳腺癌患者中产生了2例部分缓解；3例患者出现发热性中性粒细胞减少，2例患者出现II级黏膜炎。多西他赛/长春瑞滨联合用药方案作为转移性乳腺癌的一线治疗方案在所有剂量水平均产生了缓解；2例患者出现剂量限制性毒性，但仅在长春瑞滨剂量提高到22.5mg/m²时出现。在非小细胞肺癌的II期研究中，初步结果表明多西他赛/顺铂联合用药方案具有有前景的活性水平和可接受的毒性特征。未来的试验将继续评估多西他赛在联合用药和序贯用药方案中的作用，尤其是在转移性乳腺癌和非小细胞肺癌中。
