PDF(Pubmed)
Abstract：
This pre-clinical study was designed to demonstrate how vascular disrupting agents (VDAs) should be administered, either alone or when combined with radiation in clinically relevant fractionated radiation schedules, for the optimal anti-tumor effect. CDF1 mice, implanted in the right rear foot with a 200 mm3 murine C3H mammary carcinoma, were injected with various doses of the most potent VDA drug, combretastatin A-1 phosphate (CA1P), under different schedules. Tumors were also locally irradiated with single-dose, or stereotactic (3 × 5-20 Gy) or conventional (30 × 2 Gy) fractionation schedules. Tumor growth and control were the endpoints used. Untreated tumors had a tumor growth time (TGT5; time to grow to 5 times the original treatment volume) of around 6 days. This increased with increasing drug doses (5-100 mg/kg). However, with single-drug treatments, the maximum TGT5 was only 10 days, yet this increased to 19 days when injecting the drug on a weekly basis or as three treatments in one week. CA1P enhanced radiation response regardless of the schedule or interval between the VDA and radiation. There was a dose-dependent increase in radiation response when the combined with a single, stereotactic, or conventional fractionated irradiation, but these enhancements plateaued at around a drug dose of 25 mg/kg. This pre-clinical study demonstrated how VDAs should be combined with clinically applicable fractionated radiation schedules for the optimal anti-tumor effect, thus suggesting the necessary pre-clinical testing required to ultimately establish VDAs in clinical practice.
摘要：
这项临床前研究旨在证明应如何使用血管破坏剂（VDA）。单独或在临床相关的分割放射时间表中与放射结合时，以获得最佳的抗肿瘤效果。CDF1小鼠,在右后脚植入200mm3小鼠C3H乳腺癌，注射了各种剂量的最有效的VDA药物，康布他汀A-1磷酸盐（CA1P），根据不同的时间表。肿瘤也用单剂量局部照射，或立体定向（3×5-20Gy）或常规（30×2Gy）分馏时间表。肿瘤生长和对照是使用的终点。未治疗的肿瘤具有约6天的肿瘤生长时间(TGT5;生长至原始治疗体积的5倍的时间)。这随着药物剂量的增加(5-100mg/kg)而增加。然而,用单一药物治疗，最长的TGT5只有10天，然而，当每周注射药物或一周三次治疗时，这一数字增加到19天。CA1P增强了辐射响应，而与VDA和辐射之间的时间表或间隔无关。当与单个，立体定向,或传统的分馏辐照，但是这些增强在25mg/kg的药物剂量附近稳定。这项临床前研究证明了如何将VDA与临床适用的分次放射时间表相结合，以获得最佳的抗肿瘤效果。因此，建议在临床实践中最终建立VDA所需的必要的临床前测试。
