Berko R, Seissman K, Colvin M, Bocian R C, Ben-Efraim S, Dray S
Department of Microbiology and Immunology, University of Illinois, Chicago 60680.
Int J Immunopharmacol. 1988;10(7):825-34. doi: 10.1016/0192-0561(88)90006-9.
The effectiveness of a relatively low dose of cyclophosphamide (15 mg/kg CY), melphalan (2.5 mg/kg L-PAM) or the monofunctional form of CY (150 mg/kg MoCY) for the cure of mice bearing a large primary s.c. MOPC-315 tumor and extensive metastases has been shown to be dependent on the cooperation of the drugs' tumoricidal activity with T-cell-dependent antitumor immunity, the latter facilitated by the drug's immunomodulatory activity. Here, we have compared the curative effectiveness of three additional drugs: methyl nitrosourea (MNU), hydroxyurea (OH-urea) and bis-chloroethyl nitrosourea (BCNU). Among these drugs, only a relatively low dose of BCNU (15-20 mg/kg) was effective in curing most mice (85%) bearing a large, late stage tumor. A higher dose of BCNU (40 mg/kg, LD10) was much less effective. After an optimal dose of BCNU, the proliferative capacity of the tumor cells 24 h after therapy was reduced by greater than 97%. However, viable tumorigenic cells were still present in the primary tumor and enhanced T-cell-dependent antitumor immunity was necessary for their eradication. The cured mice were resistant to tumor rechallenge. When a low curative dose of L-PAM was followed by OH-urea, the therapeutic effectiveness was not affected, but when this dose of L-PAM was followed by a high nontoxic dose of MNU (100-150 mg/kg), the therapeutic effectiveness was diminished even though MNU was highly tumoricidal (i.e. greater than 99% inhibition of proliferative activity). Thus, BCNU appears to be similar to CY, L-PAM and MoCY in its mechanism of MOPC-315 tumor eradication. The alkylating activity of CY, L-PAM, MoCY and BCNU appears to be critical for their combined tumoricidal and immunomodulatory effects. Since BCNU is the simplest of these four drugs with respect to metabolic pathway, a further study with BCNU and related constructs may shed some light on the biochemical mechanisms of their mode of action. At least one reason for the ineffectiveness of OH-urea or MNU at either low or nontoxic high doses was poor tumoricidal or immunomodulatory activity, respectively. Thus, it seems important to consider both the tumoricidal and immunomodulatory activities of drugs when developing regimens for effective chemotherapy.
已证明，相对低剂量的环磷酰胺（15毫克/千克CY）、美法仑（2.5毫克/千克L-PAM）或单功能形式的CY（150毫克/千克MoCY）对治愈患有大型原发性皮下MOPC-315肿瘤及广泛转移的小鼠有效，其有效性取决于药物的杀肿瘤活性与T细胞依赖性抗肿瘤免疫的协同作用，后者因药物的免疫调节活性而得到促进。在此，我们比较了另外三种药物的治疗效果：甲基亚硝基脲（MNU）、羟基脲（OH-脲）和双氯乙基亚硝基脲（BCNU）。在这些药物中，只有相对低剂量的BCNU（15 - 20毫克/千克）能有效治愈大多数（85%）患有大型晚期肿瘤的小鼠。更高剂量的BCNU（40毫克/千克，LD10）效果则差得多。给予最佳剂量的BCNU后，治疗24小时后肿瘤细胞的增殖能力降低了97%以上。然而，原发性肿瘤中仍存在有活力的致瘤细胞，根除这些细胞需要增强T细胞依赖性抗肿瘤免疫。治愈的小鼠对肿瘤再次攻击具有抗性。当低治疗剂量的L-PAM后接着给予OH-脲时，治疗效果不受影响，但当此剂量的L-PAM后接着给予高剂量无毒的MNU（100 - 150毫克/千克）时，即使MNU具有高度杀肿瘤活性（即增殖活性抑制大于99%），治疗效果仍会降低。因此，BCNU在根除MOPC-315肿瘤的机制上似乎与CY、L-PAM和MoCY相似。CY、L-PAM、MoCY和BCNU的烷基化活性似乎对它们联合的杀肿瘤和免疫调节作用至关重要。由于就代谢途径而言，BCNU是这四种药物中最简单的一种，对BCNU及相关构建体的进一步研究可能会揭示它们作用方式的生化机制。羟基脲或MNU在低剂量或无毒高剂量时无效的至少一个原因分别是杀肿瘤活性差或免疫调节活性差。因此，在制定有效的化疗方案时，考虑药物的杀肿瘤和免疫调节活性似乎很重要。
