Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel
Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel
复制标题
DOI：
10.1093/jnci/88.18.1308
复制
发表时间：
1996-09-18
影响因子：
10.3
通讯作者：
Milas, L
中科院分区：
文献类型：
--
作者：
Milross, CG;Mason, KA;Milas, L
背景资料：微管是细胞器，其功能包括通过有丝分裂控制细胞分裂、细胞形态和细胞内物质的运输。抗癌药物紫杉醇（Taxol）促进过度稳定的微管的加速组装。因此，经处理的细胞倾向于在有丝分裂中被阻滞。该药物还在体外和体内诱导凋亡性细胞死亡。在本研究之前，尚未确定有丝分裂阻滞和细胞凋亡对体内抗肿瘤作用的相对贡献以及两个因素之间的关系;此外，尚不清楚紫杉醇诱导的有丝分裂阻滞是否不可避免地导致细胞死亡。目的：我们的目的是量化紫杉醇在16种小鼠肿瘤中诱导的有丝分裂阻滞和凋亡，并将这两个因素与药物的抗肿瘤作用相关联。研究方法：向近交系C3 Hf/Kam小鼠植入以下16种同基因肿瘤之一：7种腺癌（MCa-4、MCa-29、MCa-35、MCa-K、OCa-I、ACa-SG和HCa-I）、2种鳞状细胞癌（SCC-IV和SCC-VIP）、6种肉瘤（FSa、FSa-II、Sa-IIa、Sa-NH、NFSa和Sa-4020）和1种淋巴瘤（Ly-TH）。在163只对照螨和163只给药螨中测定紫杉醇（静脉注射38 mg/kg体重）诱导的Turner生长延迟，并通过Student t检验评估其显著性。在另一组439只小鼠中，紫杉醇给药后不同时间对有丝分裂或凋亡细胞的百分比进行显微形态学评分。紫杉醇诱导肿瘤生长相关性的意义。延迟和紫杉醇诱导的有丝分裂或凋亡水平通过简单相关和斯皮尔曼等级相关来确定，报道的P值代表统计学显著性的双侧检验。结果如下：四分之三的小鼠乳腺癌对紫杉醇治疗的反应中发现了统计学显著的肿瘤生长延迟（所有p均小于或等于.010），卵巢癌（P =.00003），涎腺腺癌（P = 0.0002），淋巴瘤（P = 0.0002），以及6例肉瘤中的2例（P均小于或等于0.034），但两例鳞状细胞癌或肝细胞癌均不存在。紫杉醇诱导的有丝分裂阻滞在所有类型的肿瘤中都很明显，但程度不同，与生长延迟无显著相关性（R（2）= 0.16; P = 0.124）。相反，紫杉醇引起的凋亡性细胞死亡并不普遍，但与生长延迟密切相关（R（2）=，59; P> =.001）。细胞凋亡的预处理水平与紫杉醇诱导的细胞凋亡（R（2）= 0.71; P = 0.00084）和肿瘤生长延迟（R（2）= 0.55; P = 0.001）相关。结论：紫杉醇的抗肿瘤作用与紫杉醇诱导的细胞凋亡和基线凋亡有关，而与细胞分裂阻滞无关。细胞凋亡是紫杉醇治疗小鼠肿瘤的一个重要机制。预处理和紫杉醇诱导的细胞凋亡之间的相关性暗示了潜在的特纳型特异性细胞凋亡倾向。预处理细胞凋亡的程度和紫杉醇诱导的细胞凋亡的百分比可能是有用的预测药物的反应。
Background: Microtubules are cellular organelles with functions that include control of cell division by mitosis, cell morphology, and transport of material within the cell. The anticancer drug paclitaxel (Taxol) promotes accelerated assembly of excessively stable microtubules. Consequently, treated cells tend to become arrested in mitosis. The drug also induces apoptotic cell death in vitro and in vivo. Prior to this study the relative contributions of mitotic arrest and apoptosis to the in vivo antitumor effect and the relationship between the two factors had not been established; moreover, it is not known whether paclitaxel-induced mitotic arrest inevitably results in cell death. Purpose: Our aim was to quantify the mitotic arrest and apoptosis induced by paclitaxel in 16 murine tumors in vivo and to correlate these two factors with the drug's antitumor effect. Methods: Inbred C3Hf/Kam mice were implanted with one of the following 16 syngeneic tumors: seven adenocarcinomas (MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VIP), six sarcomas (FSa, FSa-II, Sa-IIa, Sa-NH, NFSa, and Sa-4020), and one lymphoma (Ly-TH). The turner growth delay induced by paclitaxel (38 mg/kg body weight given intravenously) was measured in 163 control and 163 treated mite, and its significance was assessed by Student's t test. In a separate group of 439 mice, the percentage of cells in mitosis or apoptosis was scored micromorphometrically at various times after paclitaxel administration. The significance of correlations between paclitaxel-induced tumor growth. delay and paclitaxel-induced levels of mitosis or apoptosis was determined by simple correlation and Spearman's rank correlation, P values reported represent two-sided tests of statistical significance. Results: Statistically significant tumor growth delays were found in response to paclitaxel treatment of mice for three of four murine mammary carcinomas (all p less than or equal to.010), an ovarian carcinoma (P =.00003), a salivary gland adenocarcinoma (P = .0002), a lymphoma (P =.0002), and two of six sarcomas (both P less than or equal to.034), but not for either of two squamous cell carcinomas or for the hepatocellular carcinoma. Paclitaxel-induced mitotic arrest was apparent in all tumor types, but to various degrees, and was not significantly correlated with growth delay (R(2) = .16; P =.124). In contrast, apoptotic cell death in response to paclitaxel was not ubiquitous, but it was strongly correlated with growth delay (R(2) =,59; P> =.001). The pretreatment level of apoptosis was correlated with both pacliltaxel-induced apoptosis (R(2) =.71; P =.00084) and tumor growth delay (R(2) =.55; P =.001). Conclusion: The antitumor effect of paclitaxel was correlated with paclitaxel-induced apoptosis and base-line apoptosis, but not with mitotic arrest. Implications: Apoptosis is an important mechanism of cell death in response to paclitaxel treatment of in vivo murine tumors. An underlying turner type-specific propensity for apoptosis is implied by the correlation between pretreatment and paclitaxel-induced apoptosis. Both the extent of pretreatment apoptosis and the paclitaxel-induced percentage of apoptosis may be useful predictors of response to the drug.