Fellous A, Ohayon R, Vacassin T, Binet S, Lataste H, Krikorian A, Couzinier J P, Meininger V
Inserum U96, Hôpital de Kremlin-Bicêtre, Bicetre, France.
Semin Oncol. 1989 Apr;16(2 Suppl 4):9-14.
Navelbine (NVB) or 5' nor-anhydro-vinblastine was shown to present a broader antitumor activity and to induce fewer side effects than vinblastine (VBL) or vincristine (VCR). The possible mechanisms of these differences were analyzed with in vitro methods. At substoichiometric concentrations, the three drugs inhibit microtubule assembly. NVB, in comparison with VCR and VBL, is shown to have a lower inhibitory effect. At stoichiometric concentrations, the three drugs are able to induce tubulin aggregation into spirals and paracrystals. This process involves a microtubule-associated protein (MAPs) family referred to as Tau and is inhibited by another MAPs family referred to as MAP2. However, dramatic quantitative and qualitative differences are observed between NVB and VLB or VCR in TAU-induced aggregation of tubulin. The rate and extent of NVB-induced tubulin aggregation is much lower. With NVB, only certain TAU isoforms are able to induce paracrystals, while all TAU isoforms may contribute to VCR-induced or VBL-induced paracrystals. The TAU isoforms that are not able to induce crystallization with NVB, at least in a certain range of concentrations, are probably involved in mitotic microtubules--the hypothetical antitumoral target of vinca alkaloids (VAS). The present work shows for the first time that an anticancer drug is able to discriminate between the various types of microtubules. A next step will be to investigate whether this property is limited to a modulating effect of the various TAU isoforms on the affinity of VAS for tubulin. These biochemical investigations will be extended to tubulins extracted from tumor cell lines in order to further discriminate NVB from the other VAS.
诺维本（NVB）或5' - 去甲 - 脱水长春碱显示出比长春碱（VBL）或长春新碱（VCR）具有更广泛的抗肿瘤活性且副作用更少。用体外方法分析了这些差异的可能机制。在亚化学计量浓度下，这三种药物均抑制微管组装。与VCR和VBL相比，NVB显示出较低的抑制作用。在化学计量浓度下，这三种药物能够诱导微管蛋白聚集成螺旋体和副晶体。这个过程涉及一个称为Tau的微管相关蛋白（MAPs）家族，并受到另一个称为MAP2的MAPs家族的抑制。然而，在TAU诱导的微管蛋白聚集方面，观察到NVB与VLB或VCR之间存在显著的定量和定性差异。NVB诱导的微管蛋白聚集的速率和程度要低得多。对于NVB，只有某些TAU亚型能够诱导副晶体形成，而所有TAU亚型都可能促成VCR或VBL诱导的副晶体形成。至少在一定浓度范围内不能与NVB诱导结晶的TAU亚型可能参与有丝分裂微管——长春花生物碱（VAS）的假定抗肿瘤靶点。本研究首次表明一种抗癌药物能够区分不同类型的微管。下一步将研究这种特性是否仅限于各种TAU亚型对VAS与微管蛋白亲和力的调节作用。这些生化研究将扩展到从肿瘤细胞系中提取的微管蛋白，以便进一步区分NVB与其他VAS。
