Rowinsky E K
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78229, USA.
Drugs. 2000;60 Suppl 1:1-14; discussion 41-2. doi: 10.2165/00003495-200060001-00001.
There have been extraordinary advances in anticancer therapy over the last few decades, particularly for patients with relatively uncommon malignancies, largely because of the advent of nonspecific cytotoxic chemotherapeutics. Although these agents have also brought improved outcomes for patients with many of the more common solid cancers, it is clear that the point of 'diminishing return' has been reached. The recent development of a plethora of rationally designed target-based anticancer agents has opened up new opportunities and extraordinary therapeutic challenges. Since these agents appear primarily to target malignant cells, they can be expected to be less toxic at clinically effective doses than the cytotoxic agents. Among the various types of rationally designed target-based agents are those that target strategic facets of cell growth signal transduction, angiogenesis, metastasis and cell cycle regulation. While the primary therapeutic benefit of these agents is expected to be decreased tumour growth, evidence suggests that objective tumour responses may also be achieved. However, because of their potentially cytostatic properties, the clinical efficacy of such biologically based agents may not be readily demonstrable with traditional phase I and II study methodologies. Additionally, their dose-toxicity relationships are likely to be less steep than those of the nonspecific cytotoxic agents, thereby rendering such concepts as the maximum tolerated dose less meaningful than alternatives such as the optimal biological dose or the biologically effective dose. Those end-points generally considered, both from a regulatory and clinical viewpoint, to be of secondary importance in trials of cytotoxic agents, such as time to disease progression, disease-related symptoms and quality of life, may evolve into primary end-points. Present findings from preclinical studies suggest that the development, evaluation and general clinical use of rationally designed target-based anticancer agents will require a radical departure from the traditional paradigms if the full potential of these new therapies is to be exploited.
在过去几十年中，抗癌治疗取得了非凡进展，特别是对于患有相对罕见恶性肿瘤的患者，这主要归功于非特异性细胞毒性化疗药物的出现。尽管这些药物也为许多更常见的实体癌患者带来了更好的治疗效果，但显然已经达到了“收益递减点”。最近大量合理设计的基于靶点的抗癌药物的开发带来了新的机遇和巨大的治疗挑战。由于这些药物似乎主要作用于恶性细胞，因此预计在临床有效剂量下它们的毒性会低于细胞毒性药物。在各种合理设计的基于靶点的药物中，有一些针对细胞生长信号转导、血管生成、转移和细胞周期调控等关键环节。虽然预计这些药物的主要治疗益处是减少肿瘤生长，但有证据表明也可能实现客观的肿瘤反应。然而，由于它们可能具有细胞抑制特性，传统的I期和II期研究方法可能无法轻易证明这类基于生物学的药物的临床疗效。此外，它们的剂量-毒性关系可能不如非特异性细胞毒性药物那样陡峭，因此最大耐受剂量等概念的意义可能不如最佳生物学剂量或生物学有效剂量等替代概念。那些从监管和临床角度来看在细胞毒性药物试验中通常被认为是次要重要性的终点，如疾病进展时间、与疾病相关的症状和生活质量，可能会演变为主要终点。临床前研究的现有结果表明，如果要充分发挥这些新疗法的潜力，合理设计的基于靶点的抗癌药物的开发、评估和一般临床应用将需要彻底背离传统模式。
