Robson H, Meyer S, Shalet S M, Anderson E, Roberts S, Eden O B
Tumour Biochemistry Laboratory, Clinical Research Department, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
Med Pediatr Oncol. 2002 Dec;39(6):573-80. doi: 10.1002/mpo.10076.
Cisplatin (cDDP), when used either alone or, more often, in combination with other agents, especially adriamycin, achieves a high response rate in osteosarcoma. Its use, however, is limited by severe nephro- and neuro-toxicity. Second generation platinum compounds, most notably carboplatin (CBDCA), have been developed in order to attempt to reduce these dose-limiting toxicities, and thus improve the therapeutic ratio. Studies evaluating the role of combination CT containing CBDCA vs. cDDP have demonstrated differing results depending on the tumor type tested and its role in the treatment of osteosarcoma has yet to be clarified.
In this study, we compared the in vitro anti-tumor activity of cDDP and CBDCA in a panel of three human osteosarcoma cell lines (HOS, MG63, and U2OS).
cDDP and CBDCA (0-20 micromol) showed marked variation in cytotoxicity among the three cell lines. EC(50) values for CBDCA in HOS and MG63 cells were approximately two-fold higher than for cDDP and the ratio of AUC(CBDCA) to AUC(cDDP) varied from 1.8 in the HOS cell line to 2.3 in the MG63 cell line. Exposure of MG63 and HOS cells to either cDDP or CBDCA (1.67 and 13.5 micromol) caused a G2/M cell cycle arrest by 24 hr. Also evident was a sub G1 peak indicative of cell death by apoptosis. U2OS cells were relatively resistant to the cytotoxic effects of both drugs, although a cell cycle arrest in response to DNA damage was observed. This suggests that unlike MG63 and HOS cells, U2OS cells have either a more efficient repair pathway for platinum-induced DNA damage or are able to evade apoptosis. Examination of apoptotic events and cellular recovery demonstrated that both an 8-16-fold higher concentration and longer treatment period for CBDCA compared with cDDP was required to produce equivalent cell death and a loss of the ability of single cell clones to form colonies in both the HOS and MG63, but not the U2OS cell line.
Our findings suggest that CBDCA at a two- to four-fold higher concentration than cDDP has potential therapeutic activity in platinum sensitive osteosarcomas, particularly when cDDP cytotoxicity compromises therapeutic efficacy.
顺铂（cDDP）单独使用或更常见的是与其他药物联合使用，尤其是阿霉素，在骨肉瘤中具有较高的缓解率。然而，其应用受到严重的肾毒性和神经毒性的限制。为了试图降低这些剂量限制性毒性，从而提高治疗指数，已开发出第二代铂类化合物，最显著的是卡铂（CBDCA）。评估含CBDCA与cDDP的联合化疗作用的研究根据所测试的肿瘤类型显示出不同的结果，其在骨肉瘤治疗中的作用尚未明确。
在本研究中，我们比较了cDDP和CBDCA在三种人骨肉瘤细胞系（HOS、MG63和U2OS）中的体外抗肿瘤活性。
cDDP和CBDCA（0 - 20微摩尔）在三种细胞系中的细胞毒性表现出显著差异。HOS和MG63细胞中CBDCA的半数有效浓度（EC(50)）值比cDDP高约两倍，且HOS细胞系中CBDCA与cDDP的曲线下面积（AUC）比值为1.8，MG63细胞系中为2.3。将MG63和HOS细胞暴露于cDDP或CBDCA（1.67和13.5微摩尔）24小时后导致G2/M期细胞周期阻滞。还明显出现了一个亚G1峰，表明细胞通过凋亡死亡。U2OS细胞对两种药物的细胞毒性相对耐药，尽管观察到其对DNA损伤有细胞周期阻滞反应。这表明与MG63和HOS细胞不同，U2OS细胞要么具有更有效的铂诱导DNA损伤修复途径，要么能够逃避凋亡。对凋亡事件和细胞恢复的检查表明，与cDDP相比，在HOS和MG63细胞系中，CBDCA产生等效细胞死亡和单细胞克隆形成集落能力丧失所需的浓度要高8 - 16倍，处理时间也要更长，但在U2OS细胞系中并非如此。
我们的研究结果表明，浓度比cDDP高两到四倍的CBDCA在铂敏感骨肉瘤中具有潜在治疗活性，特别是当cDDP的细胞毒性损害治疗效果时。
