Hwu W J, Mozdziesz D E
Department of Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Pharmacol Ther. 1997 Oct-Dec;76(1-3):101-16. doi: 10.1016/s0163-7258(97)00087-9.
The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in mice previously was shown to be markedly enhanced by co-administration of thymidine. We have examined the cellular mechanisms underlying the augmentation effect of thymidine. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma or L1210 leukemia cells in vitro. Instead, thymidine appeared to augment the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice, which specifically rejected a secondary challenge with the B16/F10 tumor. Thus, development of an antitumor immune response is facilitated by thymidine in BCNU-induced immunosuppressed mice. These preclinical studies suggested that combination therapy with alkylating agents and thymidine may be a more efficacious and less toxic anticancer therapy. The potential efficacy of the sequential administration of dacarbazine (DTIC), BCNU, and thymidine in patients with advanced malignant melanoma was investigated. As predicted from animal studies, sequential administration of DTIC, BCNU, and thymidine is a relatively nontoxic therapy for metastatic melanoma. This treatment induced durable responses in up to 35% of patients, and hence is superior to many commonly used toxic combination chemotherapies. The mechanism of action, although not well characterized, is thought to be mediated through protection of the cellular immune process, as well as organ function, from alkylating agent toxicity through modulation of DNA repair enzymes such as O(6)-alkylguanine-DNA alkyltransferase in normal tissue. Thus, thymidine is a biomodulator, which not only protects patients from hematologic, pulmonary, and hepatic toxicities associated with DTIC and BCNU chemotherapy, but also potentiates therapeutic efficacy.
先前已表明，在小鼠中，1,3-双（2-氯乙基）-1-亚硝基脲（卡莫司汀，BCNU）与胸苷共同给药时，其抗肿瘤活性会显著增强。我们研究了胸苷增强作用的细胞机制。结果发现，胸苷在体外并未增加BCNU对B16/F10黑色素瘤或L1210白血病细胞的细胞毒性。相反，胸苷似乎增强了荷瘤小鼠中肿瘤特异性细胞毒性T细胞的活性，这些小鼠能够特异性排斥B16/F10肿瘤的二次攻击。因此，胸苷可促进BCNU诱导的免疫抑制小鼠抗肿瘤免疫反应的发展。这些临床前研究表明，烷化剂与胸苷联合治疗可能是一种更有效且毒性更小的抗癌疗法。我们研究了达卡巴嗪（DTIC）、BCNU和胸苷序贯给药对晚期恶性黑色素瘤患者的潜在疗效。正如动物研究预测的那样，DTIC、BCNU和胸苷序贯给药对转移性黑色素瘤是一种相对无毒的治疗方法。这种治疗在高达35%的患者中诱导了持久反应，因此优于许多常用的毒性联合化疗。其作用机制虽然尚未完全明确，但被认为是通过保护细胞免疫过程以及器官功能，使其免受烷化剂毒性的影响，这是通过调节正常组织中的DNA修复酶如O(6)-烷基鸟嘌呤-DNA烷基转移酶来实现的。因此，胸苷是一种生物调节剂，它不仅能保护患者免受与DTIC和BCNU化疗相关的血液学、肺部和肝脏毒性，还能增强治疗效果。
