Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University, Durham, NC 27708, USA.
Int J Cancer. 2010 May 15;126(10):2448-56. doi: 10.1002/ijc.24919.
Advanced ovarian cancer has a high rate of recurrence and mortality despite relative chemosensitivity at the time of initial treatment. Conventional chemotherapeutic agents typically target rapidly dividing cells. Disease relapse may therefore result from the survival and later emergence of latent slow-proliferating and/or quiescent cancer cells. We sought to identify drugs that target this cell population and to investigate the influence of these cells on outcome of patients in remission from advanced ovarian cancer. Drugs with increased efficacy against slower proliferating cells were identified using correlation-based screening of 44,657 compounds tested on the NCI-60 panel of cancer cell lines. Validation of candidates was performed in comparison with Cisplatin or Paclitaxel and by manipulation of proliferation rates by serum deprivation. Cytostatic and cytocidal effects were evaluated using MTT assays and active caspase-3 immunocytochemistry. Ki-67 proliferation indices were determined for tumors from 104 patients in remission. UCN-01 efficacy was correlated with longer doubling time among the NCI-60 cell lines (R = 0.54, p < 0.0001) and in a panel of 24 ovarian cancer cell lines (R = 0.42, p = 0.04), whereas this was not the case for Cisplatin (R = -0.10, p = 0.65) and Paclitaxel efficacy correlated with shorter doubling time (R = -0.52, p = 0.009). Cytostatic and cytocidal effects of UCN-01 were increased in serum-deprived cells. A low proliferation index was associated with presence of persistent disease at second-look surgery (p = 0.01) and poor survival (disease-free survival, p = 0.002; overall survival, p = 0.04). These results suggest that targeting quiescent ovarian cancer cells may be a worthwhile therapeutic approach to improving survival of women with ovarian cancer.
尽管在初始治疗时具有相对的化疗敏感性，但高级卵巢癌的复发率和死亡率仍然很高。传统的化疗药物通常针对快速分裂的细胞。因此，疾病的复发可能是由于存活下来的潜伏的缓慢增殖和/或静止的癌细胞的出现。我们试图确定针对这种细胞群体的药物，并研究这些细胞对缓解期高级卵巢癌患者结局的影响。使用在 NCI-60 癌症细胞系面板上测试的 44657 种化合物的基于相关性的筛选，确定了对增殖较慢的细胞具有更高疗效的药物。通过与顺铂或紫杉醇的比较以及通过血清剥夺来操纵增殖率来验证候选药物。使用 MTT 测定法和活性 caspase-3 免疫细胞化学法评估细胞停滞和细胞杀伤作用。对 104 例缓解期患者的肿瘤进行 Ki-67 增殖指数测定。UCN-01 的疗效与 NCI-60 细胞系中倍增时间较长相关（R = 0.54，p <0.0001）和 24 种卵巢癌细胞系（R = 0.42，p = 0.04）相关，而顺铂（R = -0.10，p = 0.65）并非如此，紫杉醇疗效与较短的倍增时间相关（R = -0.52，p = 0.009）。UCN-01 的细胞停滞和细胞杀伤作用在血清剥夺的细胞中增加。低增殖指数与第二次手术时持续性疾病的存在相关（p = 0.01）和较差的生存相关（无病生存，p = 0.002；总生存，p = 0.04）。这些结果表明，靶向静止的卵巢癌细胞可能是改善卵巢癌女性生存的一种有价值的治疗方法。
