Saijo N, Tamura T, Nishio K
Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
Cancer Chemother Pharmacol. 2000;46 Suppl:S43-5. doi: 10.1007/pl00014049.
Numerous molecular targets of cancer chemotherapy have been identified based on progress made in molecular biology, and new categories of anticancer drugs have been developed. These include inhibitors for signal transduction, cyclin-dependent kinase, angiogenesis, and matrix metalloproteinase, gene therapy, etc. They are variously called target-based drugs, noncytotoxic drugs, or cytostatic drugs. Such drugs have interesting mechanisms of action and appear promising. However, preclinical and clinical evaluations are difficult. Some drugs have a direct antitumor effect, with demonstrated tumor shrinkage. Others show no direct cytotoxicity. The majority of recent phase I trials have evaluated the maximum tolerated dose, pharmacokinetics, adverse events, and antitumor effect. Unusual, unacceptable toxicities have been noted with some target-based drugs. Few phase I trials or preclinical studies have attempted to demonstrate target inhibition. So far very few studies has shown that there is a correlation between target inhibition and antitumor effect. In general, phase II studies are undertaken with compounds such as trastuzumab which have direct antitumor activity. Phase III trials of most target-based drugs are undertaken immediately after phase I studies since the design of appropriate phase II studies is difficult. The ultimate endpoint of phase III trials of target-based drugs is the same as that for cytotoxic drugs, such as improved cure and survival rates.
基于分子生物学取得的进展，已确定了癌症化疗的众多分子靶点，并开发了新的抗癌药物类别。这些包括信号转导抑制剂、细胞周期蛋白依赖性激酶抑制剂、血管生成抑制剂和基质金属蛋白酶抑制剂、基因治疗等。它们被分别称为基于靶点的药物、非细胞毒性药物或细胞生长抑制剂。这类药物具有有趣的作用机制，且前景看好。然而，临床前和临床评估都很困难。一些药物具有直接抗肿瘤作用，已证明可使肿瘤缩小。其他药物则无直接细胞毒性。近期的大多数I期试验评估了最大耐受剂量、药代动力学、不良事件和抗肿瘤效果。一些基于靶点的药物出现了不寻常的、不可接受的毒性。很少有I期试验或临床前研究试图证明靶点抑制作用。到目前为止，很少有研究表明靶点抑制与抗肿瘤效果之间存在关联。一般来说，II期研究针对具有直接抗肿瘤活性的化合物进行，如曲妥珠单抗。大多数基于靶点的药物在I期研究后立即进行III期试验，因为设计合适的II期研究很困难。基于靶点的药物III期试验的最终终点与细胞毒性药物相同，如提高治愈率和生存率。
