Jackson R C
Chemotherapy Department, Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105.
NCI Monogr. 1987(5):9-15.
Despite extensive knowledge of the molecular basis for anticancer selectivity of antifolates, particularly classical antifolates, several fundamental questions remain unanswered. It is still not known why antifolate-treated cells die, rather than remain in stasis. The role of uracil misincorporation into DNA in causing irreparable damage has not yet been completely clarified, nor to what extent the antipurine effect of methotrexate (MTX) may be a desirable effect that contributes to antitumor activity. The antipurine effect may cause progression delay, with paradoxical "self-antagonism"; possibly the antipurine effect of MTX is a cause of toxic side effects. Even less is known about the molecular pharmacology of nonclassical antifolates. If they are not dependent for cellular uptake upon a neoplastic transformation-linked carrier, and since they are not subject to polyglutamylation, the molecular basis for anticancer selectivity of nonclassical antifols is unclear. The mechanism by which trimetrexate and metoprine are transported into cells is not known; if it is by passive diffusion, it is odd that resistance is sometimes associated with impaired drug uptake. Other unanswered questions are the mechanism of cross-resistance of doxorubicin-resistant cells to trimetrexate, and why the cytotoxic effect of trimetrexate, at low concentrations, is reversed by thymidine in the absence of purines. Questions also remain concerning antifolate inhibitors of thymidylate synthase (TS), such as how 5,8-dideaza-10-propargylfolic acid (CB3717) enters cells, and whether TS inhibitors will have activity against slowly growing tumors. These and related questions are discussed in relation to the design of optimal antifolate chemotherapy.
尽管人们对抗叶酸剂（尤其是经典抗叶酸剂）抗癌选择性的分子基础已有广泛了解，但仍有几个基本问题未得到解答。目前仍不清楚为什么经抗叶酸剂处理的细胞会死亡，而不是停滞不前。尿嘧啶错误掺入DNA导致不可修复损伤的作用尚未完全阐明，甲氨蝶呤（MTX）的抗嘌呤作用在多大程度上可能是有助于抗肿瘤活性的理想效应也不清楚。抗嘌呤作用可能导致进展延迟，并伴有矛盾的“自我拮抗”；MTX的抗嘌呤作用可能是毒性副作用的一个原因。对于非经典抗叶酸剂的分子药理学了解更少。如果它们的细胞摄取不依赖于与肿瘤转化相关的载体，而且由于它们不会发生多聚谷氨酸化，那么非经典抗叶酸剂抗癌选择性的分子基础就不清楚。三甲曲沙和美托普林进入细胞的机制尚不清楚；如果是通过被动扩散，那么耐药性有时与药物摄取受损相关就很奇怪。其他未解答的问题包括多柔比星耐药细胞对三甲曲沙的交叉耐药机制，以及为什么在没有嘌呤的情况下，低浓度的三甲曲沙的细胞毒性作用会被胸腺嘧啶逆转。关于胸苷酸合成酶（TS）的抗叶酸抑制剂也存在问题，比如5,8 - 二去氮 - 10 - 炔丙基叶酸（CB3717）如何进入细胞，以及TS抑制剂对生长缓慢的肿瘤是否有活性。本文将结合最佳抗叶酸化疗方案的设计来讨论这些及相关问题。
