Belt J A, Marina N M, Phelps D A, Crawford C R
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38101.
Adv Enzyme Regul. 1993;33:235-52. doi: 10.1016/0065-2571(93)90021-5.
The permeation of nucleosides across the plasma membrane of mammalian cells is complex and mediated by at least five distinct transporters that differ in their sensitivity to inhibitors and in their specificity for nucleosides. The basic properties and permeant specificity of these transporters are summarized in Table 3. It appears that there may be differences in the distribution of these transporters in tumors and normal tissues that might be exploited for chemotherapeutic purposes. The human tumor cell lines examined express predominantly the NBMPR-sensitive equilibrative transporter es which can be blocked by low concentrations of NBMPR and dipyridamole. It is reasonable to expect that tumors with transport properties similar to the CCRF-CEM and Rh28 cell lines (Table 1) that have no detectable NBMPR-insensitive transport activity will be highly susceptible to the therapeutic approach of combining a transport inhibitor such as dipyridamole or NBMPR with an inhibitor of de novo pyrimidine biosynthesis. On the other hand, this approach to therapy is unlikely to succeed against tumors with transport phenotypes similar to the WI-L2 cell line that may permit the salvage nucleosides in the presence of these inhibitors. The majority of tumor cells examined, however, fall between these extremes, and it is not yet known what level of NBMPR-insensitive transport activity can be tolerated without seriously compromising this therapeutic approach. With respect to normal tissues, the mature absorptive cells of the intestine have predominantly Na(+)-dependent nucleoside transporters that are insensitive to NBMPR and dipyridamole. The proliferating crypt cells also appear to have Na(+)-dependent nucleoside transport, although they may also have an NBMPR-sensitive component of transport (Belt, unpublished data). Bone marrow granulocyte-macrophage progenitor cells also appear to have one or more concentrative nucleoside transporters. Thus these tissues, which are most vulnerable to the toxicity of antimetabolites, may be able to salvage nucleosides in the presence of inhibitors of equilibrative transport and be protected from the toxicity of de novo synthesis inhibitors. It is likely, however, that a successful application of this therapeutic approach will require the analysis of the nucleoside transport phenotype of individual tumors in order to identify those patients that may benefit from such therapy. Since the development of antibodies and cDNA probes for the various nucleoside transporters is currently underway in several laboratories, it is likely that analysis of the nucleoside transport phenotype of tumors from biopsy material will be feasible in the future.
核苷穿过哺乳动物细胞质膜的过程很复杂，至少由五种不同的转运蛋白介导，这些转运蛋白对抑制剂的敏感性以及对核苷的特异性各不相同。这些转运蛋白的基本特性和通透特异性总结于表3。肿瘤组织和正常组织中这些转运蛋白的分布可能存在差异，这或许可用于化疗目的。所检测的人类肿瘤细胞系主要表达对NBMPR敏感的平衡型转运蛋白es，低浓度的NBMPR和双嘧达莫可将其阻断。可以合理推测，具有与CCRF - CEM和Rh28细胞系（表1）相似转运特性且未检测到对NBMPR不敏感转运活性的肿瘤，对将双嘧达莫或NBMPR等转运抑制剂与嘧啶从头合成抑制剂联合使用的治疗方法会高度敏感。另一方面，对于具有与WI - L2细胞系相似转运表型的肿瘤，这种治疗方法不太可能成功，因为在存在这些抑制剂的情况下，WI - L2细胞系可能允许补救性核苷转运。然而，所检测的大多数肿瘤细胞处于这两个极端之间，目前尚不清楚在不严重影响这种治疗方法的情况下，对NBMPR不敏感的转运活性可耐受的水平是多少。关于正常组织，肠道成熟的吸收细胞主要具有对NBMPR和双嘧达莫不敏感的依赖Na⁺的核苷转运蛋白。增殖的隐窝细胞似乎也有依赖Na⁺的核苷转运，尽管它们可能也有对NBMPR敏感的转运成分（贝尔，未发表数据）。骨髓粒细胞 - 巨噬细胞祖细胞似乎也有一个或多个浓缩型核苷转运蛋白。因此，这些最易受抗代谢物毒性影响的组织，在存在平衡型转运抑制剂的情况下可能能够补救核苷，并免受嘧啶从头合成抑制剂的毒性影响。然而，这种治疗方法的成功应用可能需要分析单个肿瘤的核苷转运表型，以便确定那些可能从这种治疗中受益的患者。由于目前多个实验室正在开发针对各种核苷转运蛋白的抗体和cDNA探针，未来对活检材料中的肿瘤进行核苷转运表型分析可能是可行的。
