Ohsaki Y, Ishida S, Fujikane T, Akiba Y, Osanai S, Onodera S
First Dept. of Internal Medicine, Asahikawa Medical College.
Gan To Kagaku Ryoho. 1990 Jul;17(7):1339-43.
The development of resistance to anti-cancer drugs is a major factor in limiting the response rate of cancer chemotherapy. Several mechanisms of such resistance are reported. Recently, expression of MDR gene and synthesis of p-glycoprotein by the MDR gene was reported as a mode of multi-drug resistance, but the mechanism of the resistance to cisplatinum (CDDP) remains unclear. Detoxification of CDDP, increase of the efflux of the drug and increase of DNA repair are considered to be the mode of CDDP resistance. It is widely documented that caffeine enhances the cytocidal effect of certain anti-cancer agents. The inhibition of DNA repair by caffeine has been considered to be one mechanism which enhances the cytocidal effect of such agents. We conducted the present study to evaluate the combination effect of caffeine and CDDP on the human lung adenocarcinoma cell line PC9/P and its CDDP resistant cell line PC9/R. Cell growth inhibition was measured by clonogenic assay and cell cycle analysis was performed with propidium iodide (PI) stain using flow cytometer (FCM). Caffeine enhanced the effect of CDDP on PC9/P synergistically. However, the combination effect of the two drugs was not apparent on PC9/R. Caffeine decreased G2M accumulation due to CDDP exposure in both cell lines. The data indicate that caffeine does not overcome the resistance of PC9/R, whereas caffeine enters PC9/R. It is suggested that increase of DNA repair might not be a mode of the CDDP resistance of PC9/R.
抗癌药物耐药性的产生是限制癌症化疗反应率的一个主要因素。已有多种耐药机制被报道。最近，多药耐药基因（MDR）的表达以及该基因合成的P-糖蛋白被报道为一种多药耐药模式，但顺铂（CDDP）耐药的机制仍不清楚。CDDP的解毒、药物外排增加以及DNA修复增加被认为是CDDP耐药的模式。大量文献记载，咖啡因可增强某些抗癌药物的细胞杀伤作用。咖啡因对DNA修复的抑制作用被认为是增强此类药物细胞杀伤作用的一种机制。我们进行了本研究，以评估咖啡因与CDDP联合应用对人肺腺癌细胞系PC9/P及其CDDP耐药细胞系PC9/R的作用。通过克隆形成试验检测细胞生长抑制情况，并使用流式细胞仪（FCM）对碘化丙啶（PI）染色的细胞进行细胞周期分析。咖啡因协同增强了CDDP对PC9/P的作用。然而，两种药物的联合作用在PC9/R上并不明显。咖啡因减少了两种细胞系中由于CDDP暴露导致的G2M期细胞蓄积。数据表明，咖啡因不能克服PC9/R的耐药性，而咖啡因可进入PC9/R细胞。提示DNA修复增加可能不是PC9/R对CDDP耐药的模式。
