Fisher A M, Ferrario A, Gomer C J
Clayton Ocular Oncology Center, Childrens Hospital Los Angeles, CA.
Photochem Photobiol. 1993 Oct;58(4):581-8. doi: 10.1111/j.1751-1097.1993.tb04936.x.
Photodynamic therapy (PDT) generates reactive oxygen species that are responsible for the initial cytotoxic events produced by this treatment. An extended (16 h) porphyrin incubation prior to light irradiation increased expression of the 75, 78 and 94 kDa glucose-regulated stress proteins (GRP), as well as the cognate form of the 70 kDa heat shock protein. However, these stress proteins were not induced following isoeffective PDT doses using a short (1 h) porphyrin incubation protocol. In the current study, Chinese hamster fibroblasts were used to examine sensitivity to adjunctive PDT and adriamycin as previous reports indicate a correlation between stress protein synthesis and a decrease in adriamycin cytotoxicity. Treatments that either induced GRP (i.e. PDT with an extended porphyrin incubation or exposure to the calcium ionophore A23187) or did not induce GRP (i.e. PDT with a short porphyrin incubation or UV irradiation) were followed at increasing time intervals with a 1 h adriamycin incubation. A time-dependent decrease in adriamycin cytotoxicity was observed when cells were first exposed to either of the PDT protocols or to A23187. Alterations in intracellular drug levels did not account for the change in adriamycin sensitivity. Likewise, intracellular glutathione concentrations and antioxidant enzyme activities were not significantly altered following PDT or A23187. Parameters associated with altered adriamycin sensitivity included a decrease in the percentage of S phase cells following PDT and A23187 as well as a depletion of intracellular ATP after PDT using the extended porphyrin incubation. These results demonstrate that PDT can be added to the growing list of diverse stresses producing transient resistance to adriamycin and that stress protein induction is not universally associated with all oxidative treatments inducing this resistance.
光动力疗法（PDT）会产生活性氧，这些活性氧是该治疗产生的初始细胞毒性事件的原因。在光照前延长（16小时）卟啉孵育时间会增加75、78和94 kDa葡萄糖调节应激蛋白（GRP）以及70 kDa热休克蛋白同源形式的表达。然而，使用短（1小时）卟啉孵育方案的等效应PDT剂量后，这些应激蛋白并未被诱导。在当前研究中，使用中国仓鼠成纤维细胞来检测对辅助性PDT和阿霉素的敏感性，因为先前的报告表明应激蛋白合成与阿霉素细胞毒性降低之间存在相关性。诱导GRP的处理（即延长卟啉孵育的PDT或暴露于钙离子载体A23187）或未诱导GRP的处理（即短卟啉孵育的PDT或紫外线照射）之后，以递增的时间间隔进行1小时阿霉素孵育。当细胞首先暴露于任何一种PDT方案或A23187时，观察到阿霉素细胞毒性随时间的下降。细胞内药物水平的变化并不能解释阿霉素敏感性的变化。同样，PDT或A23187后细胞内谷胱甘肽浓度和抗氧化酶活性没有显著改变。与阿霉素敏感性改变相关的参数包括PDT和A23187后S期细胞百分比的降低以及使用延长卟啉孵育的PDT后细胞内ATP的消耗。这些结果表明，PDT可以添加到产生对阿霉素的短暂抗性的各种应激因素的不断增加的列表中，并且应激蛋白的诱导并不普遍与所有诱导这种抗性的氧化处理相关。
