How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.
How to Use a Chemotherapeutic Agent When Resistance to It Threatens the Patient.
复制标题
DOI：
10.1371/journal.pbio.2001110
复制
发表时间：
2017-02
期刊：
影响因子：
9.8
通讯作者：
Read AF
中科院分区：
文献类型：
--
作者：
Hansen E;Woods RJ;Read AF
当患者对抗癌或抗菌药物产生耐药性时，高效化疗可能会失败，威胁患者的健康和寿命。标准做法是积极治疗，尽快有效消除药物敏感的靶细胞。这防止了敏感细胞从头获得抗性，但也消除了可以竞争性抑制抗性群体的群体。在这里，我们分析了这种进化权衡，并考虑了最近的建议，即旨在遏制而不是消除肿瘤或感染的治疗方案可能更有效地延迟耐药性的出现。我们的一般数学分析表明，在某些情况下，即使没有抵抗的健身成本，旨在遏制的方案也会优于标准实践，并且在这些情况下，治疗失败的时间可能会增加一倍以上。但是，也有一些情况下，遏制措施会使不良预后变得更糟。我们的分析确定了定义这些情况的阈值，从而可以指导治疗决策。该分析还提出了多种干预措施，可与细胞毒性药物结合使用，以抑制耐药性的出现。在广泛的疾病背景下，基本原则决定了标准实践最好地延迟耐药性出现的情况，以及何时可以改善。当患者对抗癌或抗菌药物产生耐药性时，高效化疗可能会失败，威胁患者的健康和寿命。标准的做法是通过积极的化疗尽快消除敏感细胞来防止它们获得耐药性。然而，这种方法阻止了敏感细胞竞争性地抑制存在的任何抗性细胞。因此，有人建议，如果耐药性的出现威胁到患者的健康，那么应该用旨在遏制感染或癌症的方法来取代积极的治疗。在这里，我们表明，没有“一刀切”的解决方案。遏制可以改善某些情况，但也可能使事情变得更糟。我们的分析描绘了决定何时遏制是最佳选择以及何时积极治疗更好的细节。
When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to treat aggressively, effectively eliminating drug-sensitive target cells as quickly as possible. This prevents sensitive cells from acquiring resistance de novo but also eliminates populations that can competitively suppress resistant populations. Here we analyse that evolutionary trade-off and consider recent suggestions that treatment regimens aimed at containing rather than eliminating tumours or infections might more effectively delay the emergence of resistance. Our general mathematical analysis shows that there are situations in which regimens aimed at containment will outperform standard practice even if there is no fitness cost of resistance, and, in those cases, the time to treatment failure can be more than doubled. But, there are also situations in which containment will make a bad prognosis worse. Our analysis identifies thresholds that define these situations and thus can guide treatment decisions. The analysis also suggests a variety of interventions that could be used in conjunction with cytotoxic drugs to inhibit the emergence of resistance. Fundamental principles determine, across a wide range of disease settings, the circumstances under which standard practice best delays resistance emergence—and when it can be bettered. When resistance to anticancer or antimicrobial drugs evolves in a patient, highly effective chemotherapy can fail, threatening patient health and lifespan. Standard practice is to prevent sensitive cells from acquiring resistance by eliminating them as quickly as possible with aggressive chemotherapy. This approach, however, prevents sensitive cells from competitively suppressing any resistant cells that are present. Consequently, it has been suggested that where resistance emergence threatens patient health, aggressive therapies should be replaced with approaches aimed at containing the infection or cancer. Here we show that there is no “one-size-fits-all” solution. Containment can improve some situations, but it can also make things worse. Our analysis delineates the details that determine when containment is the best choice—and when aggressive treatment is better.