Gmeiner William H, Willingham Mark C, Bourland J Daniel, Hatcher Heather C, Smith Thomas L, D'Agostino Ralph B, Blackstock William
Department of Cancer Biology, Wake Forest University School of Medicine, USA.
Department of Pathology, Wake Forest University School of Medicine, USA.
J Clin Oncol Res. 2014 Jul-Aug;2(4).
Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. Here, we show that F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days = 18; p < 0.001; n = 16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity. F10 was also shown to sensitize PC3 cells to radiation and F10 was also shown to be a potent radiosensitizer of PC3 xenografts with F10 in combination with radiation resulting in significantly greater regression of PC3 xenografts than radiation alone. The results indicate that F10 in this pre-clinical setting is an effective chemotherapeutic agent and possesses significant radiosensitizing properties.
化疗在前列腺癌治疗中的应用仍然有限，只有多西他赛这一种药物对晚期疾病治疗显示出适度的生存优势。来自美国国立癌症研究所60细胞系筛选的数据表明，去势抵抗性前列腺癌细胞系PC3和DU145对新型聚合氟嘧啶（FP）F10的敏感性高于平均水平，尽管它们对广泛使用的FP 5FU的敏感性低于平均水平。在此，我们表明，与用盐水处理的对照小鼠相比，用F10处理PC3异种移植瘤可带来显著的生存优势（治疗与对照比值（T/C）天数 = 18；p < 0.001；n = 16）。通过颈静脉插管每周3次给予F10（40 mg/kg/剂量），持续5周。这种积极的给药方案完成时没有药物引起的体重减轻，也没有毒性证据。F10还被证明可使PC3细胞对辐射敏感，并且F10还被证明是PC3异种移植瘤的有效放射增敏剂，F10与辐射联合使用导致PC3异种移植瘤的消退明显大于单独使用辐射。结果表明，在这种临床前环境中，F10是一种有效的化疗药物，并具有显著的放射增敏特性。
