Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwanoha, Kashiwa, Japan.
Adv Drug Deliv Rev. 2012 Jun 1;64(8):710-9. doi: 10.1016/j.addr.2011.12.010. Epub 2011 Dec 24.
Despite great advances in cell and molecular biology, pharmacology and medicine, there is to date no antitumor drug available which can specifically kill tumor cells in the human body without damaging normal tissue, because it has not been possible to find a truly cancer specific molecule to target. Low molecular weight (MW) anticancer drugs extravasate easily from normal vessels in the body causing drug adverse effects. Conversely, high MW anti-tumor agents including antibodies against cancer cell antigens, accumulate selectively in tumors because of their leaky vasculature. However, most human solid tumors possess abundant intercellular connective tissue, hindering diffusion of such macromolecules. That is why immunoconjugate therapy for stroma rich common solid cancer has not yet proved successful in clinics. In this review, I describe a successful new strategy that overcomes the above contradictory drawbacks by conjugating a small MW cyototoxic drug with an antibody against particular components of tumor stroma. Stroma-targeting immunconjugates bound to the stroma to create a scaffold, from which sustained release of cytotoxic agent occurred and subsequently diffused throughout the tumor tissue to damage both tumor cells and tumor vessels. Cancer-stroma targeting (CAST) therapy was thus validated as a new modality of oncological therapy, especially for refractory, stromal-rich cancers.
尽管细胞和分子生物学、药理学和医学取得了巨大进展，但迄今为止，还没有一种抗肿瘤药物可以在不损伤正常组织的情况下特异性杀死人体中的肿瘤细胞，因为还没有找到真正针对癌症的特异性分子作为靶点。低分子量（MW）抗癌药物很容易从体内正常血管中外渗，导致药物不良反应。相反，包括针对癌细胞抗原的抗体在内的高分子量抗肿瘤药物由于其血管渗漏而选择性地在肿瘤中积累。然而，大多数人类实体瘤都有丰富的细胞间结缔组织，阻碍了这些大分子的扩散。这就是为什么针对富含间质的常见实体癌的免疫偶联物治疗在临床上尚未成功的原因。在这篇综述中，我描述了一种成功的新策略，该策略通过将小分子细胞毒性药物与针对肿瘤间质特定成分的抗体结合，克服了上述相互矛盾的缺点。基质靶向免疫偶联物与基质结合形成支架，细胞毒性药物从支架中持续释放，并随后扩散到整个肿瘤组织中，从而损伤肿瘤细胞和肿瘤血管。因此，癌症基质靶向（CAST）治疗被验证为一种新的肿瘤治疗模式，特别是对于难治性、富含间质的癌症。
