POTENTIATION OF DNA-ADDUCT FORMATION AND CYTOTOXICITY OF PLATINUM-CONTAINING DRUGS BY LOW PH
POTENTIATION OF DNA-ADDUCT FORMATION AND CYTOTOXICITY OF PLATINUM-CONTAINING DRUGS BY LOW PH
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DOI：
10.1002/ijc.2910540126
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发表时间：
1993-04-22
影响因子：
6.4
通讯作者：
SMETS, LA
中科院分区：
文献类型：
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作者：
ATEMA, A;BUURMAN, KJH;SMETS, LA
肿瘤组织的低间质pH值是多种抗肿瘤方式的重要调节剂。为了探索低pH对顺式和卡铂细胞毒活性增强作用的最佳条件，我们研究了L1210小鼠白血病细胞中药物活性和pH调节的时间方面，并与各种其他药物进行了比较。在药物暴露前、暴露中、暴露后调节L1210细胞胞外、胞内pH，测定L1210细胞存活率。在短时间内，顺铂和烷基化药物的细胞毒性在低pH条件下依次增强。顺铂、丝裂霉素C、美法兰和氯霉素。低pH对卡铂和阿糖胞嘧啶的细胞毒活性无影响，对阿霉素的作用有抑制作用。在低pH下的长时间孵育过程中，顺铂的增强作用增加，卡铂的增强作用超过3倍。卡铂暴露4小时后，在低pH的无药培养基中培养20小时，也表现出部分后一种效果。孵育后不增加低pH对美法兰和顺铂细胞毒活性的刺激作用。酸化既不影响含铂药物的摄取，也不影响含铂药物的胞外水解。在所有情况下，通过免疫细胞化学检测，含铂药物的增强都伴随着铂诱导的DNA修饰的增加。
The low interstitial pH of tumor tissue is an important modulator of various anti-tumor modalities. In order to explore the optimal conditions for the potentiating action of low pH on the cytotoxic activities of cis- and carbo-platin, we have investigated the temporal aspects of drug activity and pH modulation in L1210 murine leukemia cells in comparison with various other drugs. Extra- and intra-cellular pH of L1210 cells was modulated before, during and after drug exposure and survival of L1210 cells was determined. During short exposures, cytotoxicity of cisplatin and alkylating drugs was potentiated by conditions of low pH in the ranking order of. cisplatin, mitomycin C, melphalan and chlorambucil. Low pH had no effect on the cytotoxic activity of carboplatin and cytosine arabinoside and it inhibited the action of doxorubicin. During prolonged incubation at low pH, potentiation of cisplatin was increased and a more than 3-fold potentiation was induced in the case of carboplatin. Part of the latter effect was also manifested by 20 hr post-incubation in drug-free medium at low pH after a 4-hr exposure to carboplatin. Post-incubation did not increase the stimulating effect of low pH on the cytotoxic activity of melphalan and cisplatin. Acidification affected neither the uptake nor the extracellular hydrolysis of platinum-containing drugs. Under all circumstances, potentiation of platinum-containing drugs was accompanied by an increase in platinum-induced DNA modification, as detected by immunocytochemistry.