Preclinical antitumor activity of the oral platinum analog satraplatin
Preclinical antitumor activity of the oral platinum analog satraplatin
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DOI：
10.1007/s00280-007-0502-z
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发表时间：
2007-09-01
影响因子：
3
通讯作者：
Caligiuri, Maureen
中科院分区：
文献类型：
--
作者：
Wosikowski, Katja;Lamphere, Lou;Caligiuri, Maureen
目的：沙特铂是一种口服的铂类似物。本研究的目的是更好地表征沙特铂在多种敏感和耐药的人类肿瘤细胞系和前列腺癌异种移植模型中的临床前抗肿瘤疗效，并评估沙特铂对前列腺癌细胞系中PSA表达和/或分泌的影响。方法临床前检测沙特铂及其主要代谢物JM-118对人前列腺、NCI药物筛选组和耐药肿瘤细胞的细胞毒活性。同时，在人前列腺癌模型中对沙特铂的抗增殖效果进行了体内试验。采用实时荧光定量PCR检测沙特铂和JM-118对PSA转录的影响。结果沙特铂和JM-118在体外和体内均能抑制前列腺癌细胞的生长，并呈剂量依赖性。沙铂对雄激素不敏感细胞的IC50毒性值为1 ~ 3 μ M，对雄激素敏感细胞系的IC50毒性值为11 μ M。有趣的是，JM-118的效力是沙特铂的16倍。口服沙特铂对裸鼠PC-3异种移植模型可抑制这些人类肿瘤的生长。沙特铂对PSA转录无直接影响，所观察到的PSA分泌减少与细胞数量减少相关。当在NCI药物筛选小组中进行评估时，沙特铂在白血病和小细胞肺癌细胞系中最活跃。对沙特铂和JM-118对化疗药物耐药的细胞进行了试验。沙特铂和JM-118在顺铂耐药的A129cp80卵巢癌细胞系中具有相同的活性，活性与在亲本系中观察到的活性相当。MDR1、BCRP、MRP1的表达、微管蛋白或拓扑异构酶I的改变均未发现介导对沙铂或JM-118的耐药。尽管这些耐药机制有助于许多化疗药物的耐药，但它们似乎并未在沙特铂耐药中发挥作用。结论沙特铂和JM-118在人前列腺癌及其他肿瘤中具有临床前抗肿瘤活性，包括对顺铂、多西紫杉醇和米托蒽酮耐药的多种细胞系。此外，研究结果提示，PSA作为沙特铂治疗前列腺癌患者临床反应的相关标志物还有待进一步评估。
Purpose Satraplatin is an orally available platinum analog. The purpose of this study was to better characterize satraplatin's preclinical antitumor efficacy in a variety of sensitive and resistant human tumor cell lines and in a prostate cancer xenograft model and to evaluate the effect of satraplatin on PSA expression and/or secretion in a prostate cancer cell line.Methods Satraplatin and its primary metabolite JM-118 were preclinically tested for their cytotoxic activity in a range of cancer cells including: human prostate, those forming the NCI drug screening panel, and those resistant to anti-cancer drugs. Also, the antiproliferative efficacy of satraplatin was tested in vivo in a human prostate cancer model. The effect of satraplatin and JM-118 on PSA transcription was measured by quantitative real time PCR.Results Satraplatin and JM-118 inhibited in vitro and in vivo the growth of prostate cancer cells in a dose-dependent fashion. The IC50 cytotoxicity values for satraplatin ranged from 1 to 3 mu M for androgen-insensitive cells and was 11 mu M for the androgen-sensitive cell line. Interestingly, JM-118 was up to 16-fold more potent than satraplatin. Oral administration of satraplatin to nude mouse PC-3 xenograft models inhibited the growth of these human tumors. Satraplatin had no direct effect on PSA transcription and the observed decrease in secreted PSA correlated with a decrease in cell number. When evaluated in the NCI drug-screening panel, satraplatin was most active in leukemia and small cell lung cancer cell lines.Both satraplatin and JM-118 were tested on cells resistant to chemotherapeutic agents. Satraplatin and JM-118 were equally active in the cisplatin-resistant A129cp80 ovarian carcinoma cell line, with activity comparable to that observed in the parent line. Neither expression of MDR1, BCRP, MRP1, nor altered tubulin or topoisomerase I were found to mediate resistance to satraplatin or JM-118. Although these resistance mechanisms contribute to drug resistance for a number of chemotherapeutics, they do not appear to play a role in satraplatin resistance.Conclusions These results demonstrate that satraplatin and JM-118 have preclinical antitumor activity in human prostate cancer and other tumor types as well, including several cell lines displaying drug resistance to cisplatin, docetaxel and mitoxantrone. In addition, the results suggest that PSA should be further evaluated as a relevant marker of clinical response in patients with prostate cancer treated with satraplatin.