Chemotherapy is central to oncology, perceived to operate only on prolific cancerous tissue. Yet, many non-neoplastic tissues are more prolific compared with typical tumors. Chemotherapies achieve sufficient therapeutic windows to exert antineoplastic activity because they are prodrugs that are bioactivated in cancer-specific environments. The advent of precision medicine has obscured this concept, favoring the development of high-potency kinase inhibitors. Inhibitors of essential mitotic kinases exemplify this paradigm shift, but intolerable on-target toxicities in more prolific normal tissues have led to repeated failures in the clinic. Proliferation rates alone cannot be used to achieve cancer specificity. Here, we discuss integrating the cancer specificity of prodrugs from classical chemotherapeutics and the potency of mitotic kinase inhibitors to generate a class of high-precision cancer therapeutics.

化疗是肿瘤学的核心，被认为仅对多产的癌组织起作用。然而，与典型肿瘤相比，许多非肿瘤组织更加多产。化学疗法实现了足够的治疗窗口以发挥抗肿瘤活性，因为它们是在癌症特定环境中被生物激活的前药。精准医学的出现模糊了这一概念，有利于高效激酶抑制剂的开发。必需有丝分裂激酶的抑制剂就是这种范式转变的例证，但在更多产的正常组织中难以忍受的靶向毒性导致临床上反复失败。单独的增殖率不能用于实现癌症特异性。在这里，我们讨论将经典化疗药物前药的​​癌症特异性和有丝分裂激酶抑制剂的效力结合起来，以产生一类高精度的癌症疗法。