Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, QC, Canada, J1H 5N4.
Anticancer Res. 2013 Aug;33(8):3005-14.
Optimal conditions for efficient concomitant chemoradiation treatment of colorectal cancer with cisplatin still need to be better defined. In addition, intolerance of healthy tissue to cisplatin prevents the full exploitation of its radiosensitizing potential. A liposomal formulation of cisplatin, Lipoplatin™, was proposed to overcome its toxicity. Using an animal model of colorectal cancer, we determined the platinum window, defined by studying the pharmacokinetics and time-dependent intracellular distribution of cisplatin and Lipoplatin™.
In nude mice bearing HCT116 human colorectal carcinoma treated with cisplatin or Lipoplatin™, the platinum accumulation in blood, serum, different normal tissues, tumor and different tumor cell compartments was measured by inductively coupled plasma mass spectrometry. Radiation treatment (15 Gy) was given 4, 24, and 48 h after drug administration and was correlated to the amount of platinum-DNA adducts in the cancer cells. The resulting tumor growth delay is reported and correlated to apoptosis analysis.
The greatest effects and highest apoptosis were observed when radiation was given at 4 h or 48 h after drug injection. These times correspond to the times of maximal platinum binding to tumor DNA. An enhancement factor (ratio of group treated by combined treatment compared to chemotherapy alone) of 13.00 was obtained with Lipoplatin™, and 4.09 for cisplatin when tumor irradiation was performed 48 h after drug administration.
The most efficient combination treatment of radiation with cisplatin or Lipoplatin™ was observed when binding of platinum to DNA was highest. These results improve our understanding over the mechanisms of platinum-induced radiosensitization and should have significant impact on the design of more efficient treatment protocols.
为了使顺铂在结直肠癌的同期放化疗中达到最佳效果，仍需进一步明确最佳条件。此外，由于顺铂对健康组织的耐受性，其放射增敏潜力无法充分发挥。顺铂的脂质体制剂Lipoplatin™被提出用于克服其毒性。我们使用结直肠癌动物模型，通过研究顺铂和 Lipoplatin™的药代动力学和时间依赖性细胞内分布，确定了铂窗。
在接受顺铂或 Lipoplatin™治疗的 HCT116 人结直肠癌细胞裸鼠中，通过电感耦合等离子体质谱法测量铂在血液、血清、不同正常组织、肿瘤和不同肿瘤细胞区室中的积累。在给药后 4、24 和 48 小时给予放射治疗（15 Gy），并与癌细胞中铂-DNA 加合物的量相关。报道了由此产生的肿瘤生长延迟，并与细胞凋亡分析相关。
当在药物注射后 4 小时或 48 小时进行放射治疗时，观察到最大的效果和最高的细胞凋亡。这些时间与铂与肿瘤 DNA 结合的时间一致。当在药物给药后 48 小时进行肿瘤照射时，Lipoplatin™的增强因子（联合治疗组与单独化疗组的比值）为 13.00，顺铂为 4.09。
当铂与 DNA 的结合最高时，观察到顺铂或 Lipoplatin™与放射治疗的最有效联合治疗。这些结果提高了我们对铂诱导放射增敏机制的理解，应该对设计更有效的治疗方案产生重大影响。
