The cancer chemotherapy regimen of a taxane and platinum combination was developed more than forty years ago, yet remains the cornerstone of treatment for several major cancer types today. Although many new agents targeting cancer genes and pathways have been developed and evaluated, none have been sufficient to replace the long-established taxane/platinum combination. This leads us to ponder why, after four decades of colossal efforts, multiple discoveries, and tremendous advances in understanding gene mutations and biology, the development of conceptually superior targeted therapies has not yet achieved overwhelming success in replacing cytotoxic chemotherapy. The concept of targeted therapy is based on the idea that blocking the altered pathway(s) crucial for cancer development (and maintenance), the disturbance in cellular signaling, metabolism, and functions will make the targeted cancer cells unfit and trigger programmed cell death in cancer cells, but without the significant side effects that limit chemotherapy. We propose that the lack of anticipated triumphs of targeted therapy stems from the desensitization of programmed cell death pathways during neoplastic transformation and malignant progression of cancer cells. This renders the targeting drugs largely ineffective at killing cancer cells and mostly insufficient in clinical implements. Recent advances in understanding suggest that, in contrast to targeted therapies, taxanes and platinum agents kill cancer cells by physical rupturing nuclear membranes rather than triggering apoptosis, making their effect independent of the intrinsic cellular programmed cell death mechanism. This new recognition of the non-programmed cell death mechanism in the success of chemotherapeutic agents, such as taxanes and platinum, may inspire oncologists and cancer researchers to focus their efforts more productively on developing effective non-programmed cell death cancer therapies to replace or significantly improve the application of the current standard taxane/platinum regimens.
紫杉醇与铂类联合的癌症化疗方案在四十多年前就已确立，至今仍是多种主要癌症类型的治疗基石。尽管针对癌症基因和通路的众多新药已被研发和评估，但尚无任何一种足以取代这一历史悠久的紫杉醇/铂类联合方案。这促使我们思考：经过四十年在基因突变与生物学理解方面的巨大投入、多重发现和重大进展，为何理论上更优越的靶向疗法仍未在取代细胞毒性化疗方面取得压倒性成功？靶向疗法的核心理念在于阻断对癌症发生（及维持）至关重要的异常通路，通过干扰细胞信号传导、代谢和功能，使靶向癌细胞失活并触发程序性细胞死亡，同时避免化疗常见的严重副作用。我们认为，靶向疗法未能取得预期胜利的根源在于：癌细胞在肿瘤转化和恶性进展过程中，其程序性细胞死亡通路逐渐脱敏。这导致靶向药物在杀伤癌细胞方面效力有限，临床应用中大多效果不足。最新研究进展表明，与靶向疗法不同，紫杉醇和铂类药物通过物理性破坏核膜而非触发细胞凋亡来杀死癌细胞，其作用机制独立于细胞内在的程序性细胞死亡通路。对紫杉醇和铂类等化疗药物成功机制中非程序性细胞死亡路径的新认知，或将启发肿瘤学家和癌症研究者更有效地集中精力，开发高效的非程序性细胞死亡癌症疗法，以取代或显著改进当前标准紫杉醇/铂类方案的应用。
肿瘤(癌症)患者之家