Johnston J B, Verburg L, Shore T, Williams M, Israels L G, Begleiter A
Manitoba Cancer Treatment and Research Foundation, Winnipeg, Canada.
Leukemia. 1994 Apr;8 Suppl 1:S140-3.
The nucleoside analog, 2'-deoxycoformycin (dCF), and the alkylating agents, chlorambucil (CLB) and cyclophosphamide, are effective agents in the treatment of chronic B cell leukemias and lymphomas. The cyclophosphamide analog, 4-hydroperoxycyclophosphamide (4-HC), generates the same active metabolite as cyclophosphamide in cells and has been used extensively for bone marrow purging in vitro. We have observed that deoxyadenosine (dAdo) plus dCF (dAdo/dCF) inhibit the repair of x-irradiation-induced and bleomycin-induced DNA damage in vitro, and that this results in either synergistic or additive cytotoxicity, respectively. In the present study we examined whether dAdo/dCF, can enhance the antitumor activity of CLB and 4-HC in chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were treated with CLB for 6 hr and then with dAdo/dCF for 18 hr and cytotoxicity was measured by the MTT assay. Synergy was observed between CLB and dAdo/dCF in CLL cells from 2 patients, with synergy increasing as the CLB dose was raised. In contrast, similar treatment of human bone marrow cells resulted in little or no synergistic cell kill. Treatment of CLL cells from 2 patients with 4-HC for 30 min followed by dAdo/dCF for 18 hr resulted in little synergistic cytotoxicity, although this drug combination did produce an additive cell kill. Thus, combination therapy with nucleoside analogs and alkylating agents may be useful for improving treatment of CLL.
核苷类似物2'-脱氧助间型霉素（dCF）以及烷化剂苯丁酸氮芥（CLB）和环磷酰胺是治疗慢性B细胞白血病和淋巴瘤的有效药物。环磷酰胺类似物4-氢过氧环磷酰胺（4-HC）在细胞内产生与环磷酰胺相同的活性代谢产物，已广泛用于体外骨髓净化。我们观察到脱氧腺苷（dAdo）加dCF（dAdo/dCF）在体外可抑制X射线诱导和博来霉素诱导的DNA损伤修复，且分别导致协同或相加的细胞毒性。在本研究中，我们检测了dAdo/dCF是否能增强CLB和4-HC在体外对慢性淋巴细胞白血病（CLL）细胞的抗肿瘤活性。用CLB处理CLL细胞6小时，然后用dAdo/dCF处理18小时，通过MTT法检测细胞毒性。在2例患者的CLL细胞中观察到CLB与dAdo/dCF之间存在协同作用，且随着CLB剂量增加协同作用增强。相比之下，对人骨髓细胞进行类似处理导致很少或没有协同细胞杀伤作用。用4-HC处理2例患者的CLL细胞30分钟，然后用dAdo/dCF处理18小时，几乎没有协同细胞毒性，尽管这种药物组合确实产生了相加的细胞杀伤作用。因此，核苷类似物与烷化剂联合治疗可能有助于改善CLL治疗效果。
