Marks P A, Breslow R, Rifkind R A, Ngo L, Singh R
DeWitt Wallace Research Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Proc Natl Acad Sci U S A. 1989 Aug;86(16):6358-62. doi: 10.1073/pnas.86.16.6358.
N,N'-Hexamethylenebisacetamide (HMBA) induces transformed cells to differentiate, accompanied by suppression of oncogenicity. Clinical trials have shown that HMBA can cause positive therapeutic responses in some cancer patients, but clinical efficacy may be limited, in part, by dose-related toxicity. Potential improvements in efficacy may be accomplished by changes in the chemical structure of inducing agents and by increasing the sensitivity of tumor cells to inducers of differentiation. We have previously described an approach to improving tumor cell responsiveness to inducing agents. Transformed cell lines that have acquired low levels of resistance to vincristine display a markedly increased sensitivity to HMBA. We now report on a series of hybrid polar/apolar compounds--some of which are as active as HMBA and several of which are significantly more active than HMBA in vitro--whose chemical structures make it likely that they have different pharmacokinetics. Vincristine-resistant murine erythroleukemia cells also are shown to have marked increased sensitivity to these hybrid polar/apolar compounds. Thus these findings suggest potentially useful strategies for the application of polar/apolar inducers of differentiation to the treatment of cancers. These studies also provide approaches to further understanding of the biological process of terminal differentiation.
N，N'-亚甲基双乙酰胺（HMBA）可诱导转化细胞分化，并伴有致癌性的抑制。临床试验表明，HMBA可在一些癌症患者中引起积极的治疗反应，但临床疗效可能部分受到剂量相关毒性的限制。通过改变诱导剂的化学结构以及提高肿瘤细胞对分化诱导剂的敏感性，可能实现疗效的潜在改善。我们之前描述了一种提高肿瘤细胞对诱导剂反应性的方法。对长春新碱获得低水平抗性的转化细胞系对HMBA表现出显著增强的敏感性。我们现在报告一系列杂化极性/非极性化合物——其中一些在体外与HMBA活性相当，还有几种比HMBA活性显著更高——其化学结构使其可能具有不同的药代动力学。对长春新碱耐药的小鼠红白血病细胞对这些杂化极性/非极性化合物也表现出明显增强的敏感性。因此，这些发现提示了将极性/非极性分化诱导剂应用于癌症治疗的潜在有用策略。这些研究还为进一步理解终末分化的生物学过程提供了方法。
