Xu Lucy B, Smith Elizabeth R, Koutouratsas Vasili, Chen Zhe-Sheng, Xu Xiang-Xi
Department of Biology, University of Miami, Miami, FL 33136, USA.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Cancers (Basel). 2025 Apr 2;17(7):1208. doi: 10.3390/cancers17071208.
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.
紫杉烷与铂类联合的癌症化疗方案在四十多年前就已研发出来，但至今仍是几种主要癌症类型治疗的基石。尽管已经研发并评估了许多针对癌症基因和通路的新型药物，但尚无一种足以取代长期使用的紫杉烷/铂类联合方案。这促使我们思考，为何在经过四十年的巨大努力、多项发现以及在基因突变和生物学理解方面取得巨大进展之后，概念上更优越的靶向治疗的发展尚未在取代细胞毒性化疗方面取得压倒性成功。靶向治疗的概念基于这样一种理念，即阻断对癌症发展（和维持）至关重要的改变的通路，细胞信号传导、代谢和功能的紊乱将使靶向癌细胞不适合生存并触发癌细胞的程序性细胞死亡，但不会产生限制化疗的显著副作用。我们认为，靶向治疗缺乏预期成功的原因在于癌细胞在肿瘤转化和恶性进展过程中程序性细胞死亡通路的脱敏。这使得靶向药物在杀死癌细胞方面大多无效，在临床应用中也大多不足。最近在理解方面的进展表明，与靶向治疗不同，紫杉烷和铂类药物通过物理破坏核膜而非触发细胞凋亡来杀死癌细胞，使其作用独立于内在的细胞程序性细胞死亡机制。对紫杉烷和铂类等化疗药物成功的非程序性细胞死亡机制的这种新认识，可能会激励肿瘤学家和癌症研究人员更有成效地将精力集中在开发有效的非程序性细胞死亡癌症治疗方法上，以取代或显著改进当前标准的紫杉烷/铂类方案的应用。
