Dual-function radiation sensitizers and bioreductive drugs: factors affecting cellular uptake and sensitizing efficiency in analogues of RSU 1069.
Dual-function radiation sensitizers and bioreductive drugs: factors affecting cellular uptake and sensitizing efficiency in analogues of RSU 1069.
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双功能辐射增敏剂和生物还原药物：影响 RSU 1069 类似物细胞摄取和增敏效率的因素。
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发表时间：
1988
期刊：
影响因子：
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通讯作者：
M. Stephens
中科院分区：
文献类型：
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作者：
J. Walling;I. Stratford;G. Adams;M. Stephens
合成了低氧细胞放射增敏剂RSU 1069的烷基氮杂环丙烷类似物，其中一种含有四甲基取代氮杂环丙烷的RB 7040在体外是一种比RSU 1069更有效的增敏剂(Ahmed等人，1986)。通过测定细胞摄取这些弱碱性增敏剂在5.4-8.4范围内与细胞外介质(Phe)的pH的关系，研究了药物摄取的变化对RSU 1069及其类似物增敏效率的影响程度。V79细胞在室温下与这些药物作用1h后，细胞内外浓度(Ci/Ce)的比值(Ci/Ce)在pH为5.4时接近1。将Phe增加到8.4，RSU 1069的Ci/Ce比值没有变化(pKa=6.04)。相比之下，RSU 1165的Ci/Ce增加了3倍(pKa=7.38)，Rb 7040的Ci/Ce增加了11倍(pKa=8.45)。在研究的范围内，RSU 1069的辐射增敏作用几乎不依赖于Phe，而增加pH则导致RSU 1165和Rb 7040的增敏效率明显增加。然而，当敏化的增敏率被归一化以考虑细胞外pH对药物摄取的影响时，敏化效率与Phe无关。这项研究表明，基于对这类药物的选择性肿瘤摄取，碱性变化(PKA)可能具有更广泛的治疗潜力。
Alkyl aziridine analogues of the hypoxic cell radiosensitizer RSU 1069 have been synthesized and one of these, RB 7040, containing the tetramethyl substituted aziridine, is a more efficient sensitizer in vitro than RSU 1069 (Ahmed et al., 1986). The extent to which variation in drug uptake can influence the sensitizing efficiency of RSU 1069 and its analogues has been investigated by determining the cellular uptake of these weakly basic sensitizers as a function of the pH of the extracellular medium (pHe) over the range 5.4-8.4. Following exposure of V79 cells to these agents for 1 h at room temperature, the ratio of intra- to extracellular concentration (Ci/Ce) was near unity at pH 5.4. Increasing pHe to 8.4 resulted in no change in the ratio Ci/Ce for RSU 1069 (pKa = 6.04). In contrast, the values of Ci/Ce increased three-fold for RSU 1165 (pKa = 7.38) and eleven-fold for RB 7040 (pKa = 8.45). Radiosensitization by RSU 1069 showed little dependence on pHe over the range studied, whereas increasing pH caused an apparent increase in sensitizing efficiency of both RSU 1165 and RB 7040. However, when the enhancement ratios for sensitization were normalized to take account of the effect of extracellular pH on drug uptake, efficiency of sensitization was independent of pHe. This study suggests that changes in basicity (pKa) may have wider potential for therapeutic exploitation on the basis of selective tumour uptake for this type of agent.