Lin C K, Nguyen T T, Morgan T L, Mei R L, Kaptein J S, Kalunta C I, Yen C F, Park E, Zou H Y, Lad P M
Regional Research Laboratory, Kaiser Foundation Hospitals, 1515 N. Vermont Avenue, Los Angeles, California, 90027, USA.
Exp Cell Res. 1998 Oct 10;244(1):1-13. doi: 10.1006/excr.1998.4158.
A variety of drugs have been used to treat B-lymphocyte neoplasms, including both cell cycle-specific (CCS) and non-cell-cycle-specific drugs. Although the therapy for such cancers is complex and can include both types of drugs, the efficacy of these drugs in inducing cell death remains unclear. In this paper we have concentrated on specific CCS drugs and have examined their ability to induce programmed cell death (apoptosis) in Burkitt's lymphoma cell lines derived from patients. The CCS drugs chosen were hydroxyurea and aphidicolin (active in late G1, early S phase), the topoisomerase poisons camptothecin and etoposide (S, early G2 phase) and vincristine and Taxol (late G2, M phase). These choices allow comparison of two drugs with differing modes of action for each of the various phases of the cell cycle. Our results indicate that the variation in apoptosis between drugs that act at the same phase of the cell cycle is negligible. Both S/G2 and G2/M blockers are very potent at inducing apoptosis whereas G1/S blockers are ineffective in the induction of apoptosis. In addition, marked kinetic variations in the rate of apoptosis induction were observed, etoposide and camptothecin being more rapid in their action than the other agents. The order of effectiveness in inducing apoptosis on a kinetic basis was S/G2 agents >> G2/M agents >> G1/S agents. In this study we have also found that growth inhibition was induced by all the CCS agents chosen and by anti-IgM in various Burkitt's lymphoma lines. Furthermore c-myc was down-regulated under similar conditions. Since apoptosis was only selectively induced by some of the CCS agents, it implies c-myc expression is associated with growth regulation and c-myc down-regulation is an insufficient condition for the induction of apoptosis. In addition, cotreatments using the CCS and other agents revealed the following: Cotreatment using two CCS drugs which act at the same stage in the cell cycle showed either no change or only additivity to the effects seen with either agent alone. However, cotreatment with CCS drugs showed that an inhibitory effect is found between G1/S and G2/M drugs or S/G2 and G2/M drugs. No effect was found between G1/S and S/G2 drugs. Anti-IgM, which by itself was capable of inducing apoptosis, was observed to augment apoptosis induced by very low concentrations of G2/M-acting drugs but it has little effect on G1/S or the S/G2 drugs. The inhibitory effect of anti-CD40 or TNF-alpha on anti-IgM-induced apoptosis did not carry over to an effect on apoptosis induction by the CCS agents. Thus specific combinations of agents may lead to either enhancement, inhibition, or no interactive effect on apoptosis.
多种药物已被用于治疗B淋巴细胞肿瘤，包括细胞周期特异性（CCS）药物和非细胞周期特异性药物。尽管此类癌症的治疗很复杂，可能包括这两种类型的药物，但这些药物诱导细胞死亡的疗效仍不明确。在本文中，我们专注于特定的CCS药物，并研究了它们在源自患者的伯基特淋巴瘤细胞系中诱导程序性细胞死亡（凋亡）的能力。所选择的CCS药物有羟基脲和阿非迪霉素（作用于G1晚期、S期早期）、拓扑异构酶毒药喜树碱和依托泊苷（S期、G2期早期）以及长春新碱和紫杉醇（G2晚期、M期）。这些选择使得能够比较在细胞周期各个阶段具有不同作用模式的两种药物。我们的结果表明，作用于细胞周期同一阶段的药物之间凋亡的差异可以忽略不计。S/G2期和G2/M期阻断剂在诱导凋亡方面非常有效，而G1/S期阻断剂在诱导凋亡方面无效。此外，观察到凋亡诱导速率存在明显的动力学差异，依托泊苷和喜树碱的作用比其他药物更快。基于动力学，诱导凋亡的有效性顺序为S/G2期药物>>G2/M期药物>>G1/S期药物。在本研究中，我们还发现所选择的所有CCS药物以及抗IgM在各种伯基特淋巴瘤细胞系中均诱导生长抑制。此外，在类似条件下c-myc表达下调。由于只有一些CCS药物选择性地诱导凋亡，这意味着c-myc表达与生长调节相关，而c-myc下调是诱导凋亡的不充分条件。此外，使用CCS药物与其他药物的联合治疗显示如下情况：使用作用于细胞周期同一阶段的两种CCS药物联合治疗，与单独使用任何一种药物相比，要么没有变化，要么只有相加作用。然而，CCS药物联合治疗表明，在G1/S期和G2/M期药物之间或S/G2期和G2/M期药物之间存在抑制作用。在G1/S期和S/G2期药物之间未发现作用。抗IgM本身能够诱导凋亡，观察到它能增强极低浓度的作用于G2/M期药物诱导的凋亡，但对G1/S期或S/G2期药物几乎没有影响。抗CD40或TNF-α对抗IgM诱导凋亡的抑制作用不会延续到对CCS药物诱导凋亡的影响。因此，特定的药物组合可能导致对凋亡的增强、抑制或无相互作用效应。
