The effect of drug dose and drug exposure time on the binding, internalization, and cytotoxicity of radiolabeled somatostatin analogs.
The effect of drug dose and drug exposure time on the binding, internalization, and cytotoxicity of radiolabeled somatostatin analogs.
复制标题
药物剂量和药物暴露时间对放射性标记的生长抑素类似物的结合、内化和细胞毒性的影响。
DOI：
10.1016/j.jss.2003.06.002
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Woltering,EugeneA
中科院分区：
文献类型：
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作者：
Anthony,CatherineT;Hughey,Susan;Lyons,John;Weiss,Sean;Hornick,ConradA;Drouant,GeorgeJ;Fuselier,JosephA;Coy,DavidH;Murphy,WilliamA;Woltering,EugeneA
背景耐酶生长抑素类似物的开发使这些多肽成为临床上有用的药物。放射性标记生长抑素类似物在诊断上的广泛应用增强了人们对这些多肽的结合和细胞内分布的兴趣。药物内化的程度和药物保留的时间可能是药物诱导的细胞毒性的关键。我们假设放射性标记多肽与细胞结合、内化和诱导细胞毒性的能力与放射性配基浓度和暴露时间成正比。材料和方法为了验证这一假设，生长抑素受体表达细胞(IMR-32)与111In-喷曲肽孵育，这是一种更喜欢生长抑素类似物的SST2。放射性配基的暴露时间和/或浓度是不同的。结果长期暴露于固定浓度的放射性配基会导致整个细胞的结合和内化随着时间的推移而逐渐增加。暴露于相对固定数量的μCi-HR的细胞产生恒定的全细胞结合和内化。增加μ的Ci-HR会导致结合的比例增加。细胞毒性与辐射剂量成正比，无论是内照射(μ，Ci-HR)还是外照射(CDY)。结论在该模型中，药物暴露时间和药物浓度对细胞结合和细胞毒性均有贡献，其相对贡献呈负相关。
BACKGROUNDCreation of protease-resistant somatostatin analogs has allowed development of these peptides as clinically useful drugs. Widespread diagnostic use of radiolabeled somatostatin analogs has enhanced interest in the binding and intracellular distribution of these peptides. The degree of drug internalization and length of drug retention may be critical for drug-induced cytotoxicity. We hypothesized that the ability of a radiolabeled peptide to bind to a cell, be internalized, and induce cytotoxicity is proportional to both the radioligand concentration and the exposure time.MATERIALS AND METHODSTo test this hypothesis, somatostatin receptor-expressing cells (IMR-32) were incubated with111In-pentetreotide, a sst 2 preferring somatostatin analogue. Radioligand exposure time and/or concentration were varied.RESULTSProlonged exposure to a fixed concentration of radioligand resulted in progressive increases in whole cell binding and internalization over time. Cells exposed to a relatively fixed number of μCi-Hr yielded constant whole cell binding and internalization. Increasing the μCi-Hr resulted in a proportionate increase in binding. Cytotoxicity was also proportional to the dose of radiation regardless of whether the exposure was internalized radiation (μCi-Hr from111In-pentetreotide) or from external beam radiation (cGy).CONCLUSIONBoth drug exposure time and drug concentration contribute to cell binding and cytotoxicity in this model and their relative contributions are inversely related.