Smyth M J, Foster H M, Andrew S M, Teh J G, Krauer K, McKenzie I F, Pietersz G A
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Immunol Cell Biol. 1993 Jun;71 ( Pt 3):167-79. doi: 10.1038/icb.1993.19.
Tumour cell heterogeneity is probably a principal cause of treatment failure and represents a formidable barrier for effective antibody-targeted chemotherapy. Idarubicin (Ida), a more potent and less cardiotoxic analogue of daunomycin, has been demonstrated to specifically target and eradicate homogeneous, cloned, murine tumour cell populations in vitro and in vivo when coupled to monoclonal antibodies (MoAb); however, the antitumour activity of Ida-MoAb conjugates against human tumour xenografts remains to be established. In this study, the value of cotargeting conjugates to different human tumour-associated antigens within a solid tumour has been assessed by comparing the effects of combinations of Ida-anti-colon carcinoma MoAb conjugates with any one Ida-anti-colon carcinoma MoAb conjugate used alone. Individual Ida-MoAb conjugates have previously been evaluated for their specific binding and cytotoxicity to one of two different human colon carcinoma xenografts (Colo 205 or LIM2210) in vitro, although their efficacy alone or in combination required assessment in vivo. Combinations of the most effective Ida-MoAb conjugates were demonstrated to enable a greater number of complete tumour regressions than the most efficacious Ida-MoAb conjugate administered alone in vivo; some combinations inhibited control tumour growth by up to 95%. This study suggests that Ida-MoAb conjugates can be effective against subcutaneous human tumours in nude mice, although it is unlikely that any single conjugate will eradicate all the tumour cells in a solid tumour, and the value of 'cocktails' of drug-MoAb conjugates against some xenografts (i.e. LIM2210) appears to be limited.
肿瘤细胞异质性可能是治疗失败的主要原因，也是有效抗体靶向化疗的巨大障碍。伊达比星（Ida）是一种比柔红霉素更有效且心脏毒性更小的类似物，已证明当与单克隆抗体（MoAb）偶联时，能在体外和体内特异性靶向并根除同质的、克隆的小鼠肿瘤细胞群体；然而，Ida-MoAb偶联物对人肿瘤异种移植的抗肿瘤活性仍有待确定。在本研究中，通过比较Ida-抗结肠癌MoAb偶联物组合与单独使用任何一种Ida-抗结肠癌MoAb偶联物的效果，评估了共靶向偶联物针对实体瘤内不同人类肿瘤相关抗原的价值。此前已对单个Ida-MoAb偶联物在体外对两种不同人结肠癌异种移植瘤（Colo 205或LIM2210）之一的特异性结合和细胞毒性进行了评估，尽管其单独或联合使用的疗效需要在体内进行评估。结果表明，与单独给予体内最有效的Ida-MoAb偶联物相比，最有效的Ida-MoAb偶联物组合能使更多肿瘤完全消退；一些组合可将对照肿瘤生长抑制高达95%。本研究表明，Ida-MoAb偶联物对裸鼠皮下人肿瘤可能有效，尽管任何单一偶联物都不太可能根除实体瘤中的所有肿瘤细胞，而且药物-MoAb偶联物“鸡尾酒”对某些异种移植瘤（即LIM2210）的价值似乎有限。
