St Croix B, Man S, Kerbel R S
Biological Sciences, Division of Cancer Biology Research, Sunnybrook Health Science Centre, Toronto, ON, Canada.
Cancer Lett. 1998 Sep 11;131(1):35-44. doi: 10.1016/s0304-3835(98)00199-2.
There are two broad categories of drug resistance encountered during cancer chemotherapy, i.e. intrinsic and acquired. They are observed in virtually every type of tumor with every known anticancer chemotherapeutic drug. As such there is an urgent need to develop innovative approaches of preventing or reversing these types of resistance. One strategy to do so is to develop completely new drugs which may be resistance free, such as direct acting angiogenesis inhibitors (T. Boehm, J. Folkman, T. Browder, M.S. O'Reilly, Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance, Nature 390 (1997) 404-407; R.S. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents, BioEssays 13 (1991) 31-36; R.S. Kerbel, A cancer therapy resistant to resistance, Nature 390 (1997) 335-336). Another is to devise methods which will improve significantly the effectiveness of those conventional drugs already in use, such as adriamycin, cyclophosphamide and taxol. We have directed efforts towards the latter. They depend on the discovery of a new class of chemosensitizers which act as antiadhesive agents rendering solid tumors more susceptible to such conventional cytotoxic therapeutic drugs. Examples of this concept are illustrated with bovine testicular hyaluronidase and a mouse mammary tumor called EMT-6. When this enzyme preparation is used to treat intact multicellular spheroids of the EMT-6 tumor, the spheroids are substantially disaggregated. Dispersed spheroids are more susceptible to the cytotoxic effects of cyclophosphamide than intact spheroids. Moreover, this antiadhesive chemosensitizing effect can actually be reproduced in BALB/c mice when EMT-6 cells are grown intraperitoneally as an ascites tumor (consisting mostly of multicellular aggregates) and the mice are given injections of hyaluronidase and cyclophosphamide. In a similar fashion, the indifference of P-glycoprotein-positive multidrug-resistant EMT-6 spheroids to the P-glycoprotein reversal agent PSC-833 (a cyclosporin A analogue) can be reversed by disaggregation of the intact spheroids by hyaluronidase. This renders the treated cells highly sensitive to a combination of adriamycin and PSC-833 in a manner similar to the striking chemosensitization effects commonly observed in monolayer culture systems. Thus, hyaluronidase has the potential to reverse forms of both intrinsic and acquired drug resistance in solid tumors, such as EMT-6, which are sensitive to its antiadhesive effects.
在癌症化疗过程中会遇到两大类耐药性，即内在耐药性和获得性耐药性。几乎在每一种肿瘤类型中，使用每一种已知的抗癌化疗药物时都会观察到这两种耐药性。因此，迫切需要开发预防或逆转这些耐药类型的创新方法。一种策略是开发全新的可能无耐药性的药物，比如直接作用的血管生成抑制剂（T. 博姆、J. 福克曼、T. 布劳德、M.S. 奥赖利，《实验性癌症的抗血管生成疗法不会诱导获得性耐药》，《自然》390卷（1997年）第404 - 407页；R.S. 克尔贝尔，《抑制肿瘤血管生成作为规避对抗癌治疗药物获得性耐药的策略》，《生物论丛》13卷（1991年）第31 - 36页；R.S. 克尔贝尔，《一种抗耐药的癌症疗法》，《自然》390卷（1997年）第335 - 336页）。另一种是设计能显著提高那些已在使用的传统药物（如阿霉素、环磷酰胺和紫杉醇）有效性的方法。我们一直致力于后者。这依赖于发现一类新的化学增敏剂，它们作为抗黏附剂使实体瘤对这类传统细胞毒性治疗药物更敏感。以牛睾丸透明质酸酶和一种名为EMT - 6的小鼠乳腺肿瘤为例说明了这一概念。当用这种酶制剂处理EMT - 6肿瘤的完整多细胞球体时，球体会大量解体。分散的球体比完整的球体对环磷酰胺的细胞毒性作用更敏感。此外，当EMT - 6细胞作为腹水瘤（主要由多细胞聚集体组成）在BALB/c小鼠腹腔内生长，给小鼠注射透明质酸酶和环磷酰胺时，实际上可以在小鼠体内重现这种抗黏附化学增敏作用。以类似的方式，P - 糖蛋白阳性的多药耐药EMT - 6球体对P - 糖蛋白逆转剂PSC - 833（一种环孢素A类似物）的无反应性可以通过用透明质酸酶使完整球体解体来逆转。这使得处理后的细胞对阿霉素和PSC - 833的联合用药高度敏感，其方式类似于在单层培养系统中常见的显著化学增敏效果。因此，透明质酸酶有潜力逆转实体瘤（如EMT - 6）中内在和获得性耐药的形式，这些实体瘤对其抗黏附作用敏感。
