Davidoff A N, Mendelow B V
Department of Haematology, School of Pathology, South African Institute for Medical Research, Johannesburg.
Leuk Res. 1992 Nov;16(11):1077-85. doi: 10.1016/0145-2126(92)90046-a.
The potent effects of low doses of PM on the cell cycle have to date been obscured by the conventional usage of this drug at high concentrations (5-50 micrograms/ml) to inhibit protein synthesis. In this in vitro study undertaken in a variety of malignant and non-malignant human and murine cell types, we found that low doses of PM (0.1-0.5 microgram/ml) disrupted significant phase-to-phase cell cycle transitions, causing a G2-arrest, a metaphase-mitotic-arrest, and apoptosis. In HL-60 cells these observations were elicited by PM concentrations starting at 0.1 microgram/ml, and were more pronounced at slightly higher PM concentrations, including that (0.5 microgram/ml) which inhibited [14C]leucine incorporation by approximately 20% after one hour, and by approximately 50% after 24 h. A concentration of CHX (0.25 microgram/ml) which was equivalent to 0.5 microgram/ml of PM, both in terms of molarity (0.9 microM) and degree of inhibition of [14C]leucine incorporation, failed to induce similar changes to those induced by PM. This suggests that at these particular concentrations the PM-induced changes were likely to have been related to the different mechanisms of protein synthesis inhibition exerted by these two 'classical' translation inhibitors. PM but not CHX generates nascent peptidyl-PM complexes (PMPs), and we therefore propose that the subsequent intracellular effects exerted by the PMPs may account, in part, for the differential cytokinetic effects elicited by these drugs. The role of PM is currently being evaluated in vivo as a low-dose component of a multidrug chemotherapeutic regimen in which its cell cycle-specific effects could potentially be synergistic with other agents.
低剂量嘌呤霉素（PM）对细胞周期的显著影响，至今一直被该药物在高浓度（5 - 50微克/毫升）下用于抑制蛋白质合成的传统用法所掩盖。在这项针对多种恶性和非恶性人类及小鼠细胞类型进行的体外研究中，我们发现低剂量的PM（0.1 - 0.5微克/毫升）会干扰细胞周期从一个阶段到另一个阶段的显著转变，导致G2期阻滞、中期 - 有丝分裂期阻滞和细胞凋亡。在HL - 60细胞中，这些观察结果在PM浓度达到0.1微克/毫升时就已出现，在稍高的PM浓度下更为明显，包括0.5微克/毫升的浓度，该浓度在1小时后抑制[14C]亮氨酸掺入约20%，24小时后抑制约50%。一种氯霉素（CHX）浓度（0.25微克/毫升），在摩尔浓度（0.9微摩尔）和对[14C]亮氨酸掺入的抑制程度方面，与0.5微克/毫升的PM相当，但未能诱导出与PM所诱导的类似变化。这表明在这些特定浓度下，PM诱导的变化可能与这两种“经典”翻译抑制剂对蛋白质合成抑制的不同机制有关。PM而非CHX会生成新生肽基 - PM复合物（PMPs），因此我们提出，PMPs随后在细胞内产生的效应可能部分解释了这些药物所引发的不同细胞动力学效应。目前正在体内评估PM作为多药化疗方案低剂量成分的作用，在该方案中其细胞周期特异性效应可能与其他药物具有协同作用。
