Pietersz G A, Bogdanovski M, Li W
Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
Immunol Cell Biol. 1997 Jun;75(3):253-8. doi: 10.1038/icb.1997.39.
The antitumour efficacy of Ida-anti-Ly-2.1 immunoconjugate in combination with murine TNF-alpha (mTNF-alpha) has been evaluated in a disseminated murine thymic lymphoma model E3. This tumour model shows characteristics similar to lymphoma in humans with widely disseminated tumour in major organs. In vitro both idarubicin (Ida) and Ida-anti-Ly-2.1 showed additive and synergistic cytotoxic effects, respectively, with mTNF-alpha when tested using the isobolagram method. Similar synergistic effects were also seen in vivo. Tumour-bearing mice were treated with various doses of mTNF-alpha and Ida alone, however, neither showed a therapeutic response in mice. When mice were treated with Ida-anti-Ly-2.1 'early' the median survival time (MST) was increased by 8 days, however, 'late' treatment was ineffective. Combination therapy of mTNF-alpha and Ida-anti-Ly-2.1 conjugate (42 micrograms) given 'early' was capable of curing 50% of mice. However, when tumour-bearing mice were given a high dose (234 micrograms) of Ida-anti-Ly-2.1 together with mTNF-alpha 100% of mice survived disease free. Such an effect was not observed when free mTNF-alpha, Ida-anti-Ly-2.1, anti-Ly-2.1 or a mixture of anti-Ly-2.1+mTNF-alpha was given at the same dose. These results show that a combination of very toxic drug immunoconjugates and TNF could lead to the eradication of disseminated tumour in mice and may be relevant for the treatment of minimal residual disease in cancer patients.
已在一种播散性小鼠胸腺淋巴瘤模型E3中评估了艾达-抗Ly-2.1免疫偶联物与小鼠肿瘤坏死因子-α（mTNF-α）联合使用时的抗肿瘤疗效。该肿瘤模型显示出与人类淋巴瘤相似的特征，主要器官中存在广泛播散的肿瘤。在体外，使用等效线图法测试时，阿霉素（Ida）和艾达-抗Ly-2.1分别与mTNF-α显示出相加和协同的细胞毒性作用。在体内也观察到了类似的协同作用。给荷瘤小鼠单独使用不同剂量的mTNF-α和Ida进行治疗，然而，两者在小鼠中均未显示出治疗反应。当用艾达-抗Ly-2.1“早期”治疗小鼠时，中位生存时间（MST）增加了8天，然而，“晚期”治疗无效。“早期”给予mTNF-α和艾达-抗Ly-2.1偶联物（42微克）的联合疗法能够治愈50%的小鼠。然而，当给荷瘤小鼠同时给予高剂量（234微克）的艾达-抗Ly-2.1和mTNF-α时，100%的小鼠无病存活。当以相同剂量给予游离mTNF-α、艾达-抗Ly-2.1、抗Ly-2.1或抗Ly-2.1 + mTNF-α的混合物时，未观察到这种效果。这些结果表明，剧毒药物免疫偶联物与TNF的联合使用可能导致小鼠体内播散性肿瘤的根除，并且可能与癌症患者微小残留病的治疗相关。
