紫杉醇（泰素）是用來(lái)治療乳腺癌等多種惡性腫瘤的細(xì)胞毒性化療藥物，尤其對(duì)于主要依靠化療的三陰性乳腺癌,。不過(guò),，紫杉醇的療效如同盲盒，并非全部患者都能獲益,，其細(xì)胞毒性機(jī)制亦未完全明確,。

　　2021年9月8日，美國(guó)科學(xué)促進(jìn)會(huì)《科學(xué)》旗下《轉(zhuǎn)化醫(yī)學(xué)》在線發(fā)表威斯康星大學(xué)麥迪遜總校的研究報(bào)告,，探討了紫杉醇對(duì)乳腺腫瘤的細(xì)胞毒性機(jī)制及其療效預(yù)測(cè)指標(biāo),。

　　該研究發(fā)現(xiàn)，乳腺癌患者腫瘤內(nèi)紫杉醇濃度并不足以誘導(dǎo)腫瘤細(xì)胞有絲分裂停滯,。相反,，紫杉醇臨床治療濃度可誘導(dǎo)人類三陰性乳腺癌Cal51、MDA-MB-231細(xì)胞多極有絲分裂紡錘體形成,。不過(guò),，早期多極化程度并不能預(yù)測(cè)紫杉醇對(duì)患者的療效。多極分裂常常引起細(xì)胞死亡,，而多極紡錘體在分裂之前或多或少地集中形成雙極紡錘體,，并且在整個(gè)有絲分裂過(guò)程中保持多極對(duì)于誘導(dǎo)紫杉醇引起細(xì)胞死亡所需的染色體高度不穩(wěn)定性至關(guān)重要。紫杉醇可增加多極分裂,，導(dǎo)致細(xì)胞毒性提高,。相反,，減少紫杉醇誘導(dǎo)的多極分裂可降低紫杉醇療效,。

　　此外,，該研究發(fā)現(xiàn)已經(jīng)存在的染色體不穩(wěn)定性可使乳腺癌細(xì)胞對(duì)紫杉醇敏感，誘導(dǎo)染色體不穩(wěn)定性的基因技術(shù)和藥物都可提高紫杉醇療效,。晚期乳腺癌患者接受紫杉類治療前的染色體不穩(wěn)定性與紫杉類療效成正比,，故紫杉類治療前染色體不穩(wěn)定性較高的患者對(duì)紫杉類療效顯著較好。

　　因此,，該研究結(jié)果表明,，紫杉醇通過(guò)增加細(xì)胞分裂時(shí)的染色體錯(cuò)誤分離而產(chǎn)生細(xì)胞毒性，紫杉醇治療前的染色體不穩(wěn)定性可以作為預(yù)測(cè)紫杉醇療效的生物學(xué)標(biāo)志,。此外,，在整個(gè)有絲分裂過(guò)程中增加染色體不穩(wěn)定性或維持多極紡錘體的藥物可顯著提高紫杉醇臨床療效。

Sci Transl Med. 2021 Sep 8;13(610):eabd4811.

Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel.

Christina M. Scribano, Jun Wan, Karla Esbona, John B. Tucker, Amber Lasek, Amber S. Zhou, Lauren M. Zasadil, Ryan Molini, Jonathan Fitzgerald, Angela M. Lager, Jennifer J. Laffin, Kayla Correia-Staudt, Kari B. Wisinski, Amye J. Tevaarwerk, Ruth O'Regan, Stephanie M. McGregor, Amy M. Fowler, Richard J. Chappell, Tim S. Bugni, Mark E. Burkard, Beth A. Weaver.

University of Wisconsin-Madison, Madison, WI, USA; Wisconsin State Laboratory of Hygiene, Madison, WI, USA.

Unpacking paclitaxel response: Paclitaxel is a common treatment for many cancers, although not all patients benefit from the treatment and the mechanism by which it works is unclear. Here, Scribano et al. studied patients with breast cancer undergoing paclitaxel treatment as part of a clinical trial to elucidate the drug's mechanism of action, demonstrating that paclitaxel treatment increased cell division with chromosome missegregation to induce cytotoxicity. They also found that increased chromosomal instability in tumor cells before treatment was predictive of response to taxane therapy. Although the findings require further validation, this increased chromosomal instability may serve as a predictive biomarker for paclitaxel response in patients with breast cancer.

Paclitaxel (Taxol) is a cornerstone of cancer treatment. However, its mechanism of cytotoxicity is incompletely understood and not all patients benefit from treatment. We show that patients with breast cancer did not accumulate sufficient intratumoral paclitaxel to induce mitotic arrest in tumor cells. Instead, clinically relevant concentrations induced multipolar mitotic spindle formation. However, the extent of early multipolarity did not predict patient response. Whereas multipolar divisions frequently led to cell death, multipolar spindles focused into bipolar spindles before division at variable frequency, and maintaining multipolarity throughout mitosis was critical to induce the high rates of chromosomal instability necessary for paclitaxel to elicit cell death. Increasing multipolar divisions in paclitaxel resulted in improved cytotoxicity. Conversely, decreasing paclitaxel-induced multipolar divisions reduced paclitaxel efficacy. Moreover, we found that preexisting chromosomal instability sensitized breast cancer cells to paclitaxel. Both genetic and pharmacological methods of inducing chromosomal instability were sufficient to increase paclitaxel efficacy. In patients, the amount of pretreatment chromosomal instability directly correlated with taxane response in metastatic breast cancer such that patients with a higher rate of preexisting chromosomal instability showed improved response to taxanes. Together, these results support the use of baseline rates of chromosomal instability as a predictive biomarker for paclitaxel response. Furthermore, they suggest that agents that increase chromosomal instability or maintain multipolar spindles throughout mitosis will improve the clinical utility of paclitaxel.

DOI: 10.1126/scitranslmed.abd4811