Potentiation of ovarian OCa-1 tumor radioresponse by poly (L-glutamic acid)-paclitaxel conjugate
Potentiation of ovarian OCa-1 tumor radioresponse by poly (L-glutamic acid)-paclitaxel conjugate
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DOI：
10.1016/s0360-3016(00)00757-4
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发表时间：
2000-11-01
影响因子：
7
通讯作者：
Wallace, S
中科院分区：
文献类型：
--
作者：
Li, C;Ke, S;Wallace, S
目的：紫杉醇（TXL）能显著增强肿瘤细胞的放射敏感性。我们检查了当紫杉醇作为聚合物-药物缀合物全身递送时，其放射增敏作用是否可以进一步增强，所述聚合物-药物缀合物提供增强的肿瘤摄取和TXL在肿瘤中的延长释放。以80 mg/kg的等效TXL剂量注射聚（L-谷氨酸）-紫杉醇（PG-TXL），23小时后进行范围为5至15戈伊的单剂量局部辐射。23、48、72、120、168 h后分别以10戈伊剂量照射肿瘤，以肿瘤生长延迟法测定肿瘤的抗肿瘤活性，流式细胞术测定细胞周期分布。结果：PG-TXL能明显增强OCa-1肿瘤的放射反应。当PG-TXL先于辐射23 h时，增强因子范围为2.79 - 4.28，取决于辐射剂量。由辐射闭合响应曲线导出的增强因子高达5.13。PG-TXL的放射增敏作用也依赖于PG-TXL给药和放射递送之间的间隔，当间隔缩短时观察到更大的增强。G2/M期细胞比例在PG-TXL后38 h显著增加至21.4%，但在PG-TXL后72 h下降至注射前水平14.8%。PG-TXL、YL在24 h后仅适度增加肿瘤血管体积37%。结论：PG-TXL可明显增强OCa-1肿瘤对放射的反应。与文献报道的相同肿瘤模型比较，PG-TXL的放射增敏作用强于TXL。尽管PG-TXL的作用可能是通过阻滞细胞于G2/M期和增加肿瘤供血来介导的，但PG-TXL可能通过增加肿瘤对PC-TILL的摄取和TXL在肿瘤中的持续释放来发挥其放射增敏作用。我们的研究结果表明，TXL与聚合物的缀合具有进一步增强其放射增敏活性的潜力，并且PG-TXL与放射组合的临床试验是必要的，（C）2000 Elsevier Science Inc.
Purpose: It has been shown that paclitaxel (TXL) can strongly enhance tumor cells' sensitivity to radiation. We examined whether the radiosensitizing effect of paclitaxel can be further enhanced when it is delivered systemically as a polymer-drug conjugate that provides enhanced tumor uptake and prolonged release of TXL in the turner,Methods and Materials: C3Hf/Kam mice bearing 8-mm murine ovarian OCa-1 tumors were treated with i.v.-injected Poly(L-glutamic acid)-paclitaxel (PG-TXL) at an equivalent TXL dose of 80 mg/kg, followed 23 h later by single doses of local radiation ranging from 5 to 15 Gy, To determine how long the radiopotentiation persisted at extended times after PG-TXL administration, mice with OCa-1 tumors were given i.v. PG-TXL and 4. 23, 48, 72, 120, or 168 h later their tumors were irradiated at a dose of 10 Gy, Antitumor activity was determined by delay in tumor growth, Cell cycle distribution was assayed using how cytometry. Tumor vascular volume was estimated using Tc-99 m-labeled red blood cells,Results: PG-TXL strongly potentiated the radioresponse of the OCa-1 tumor. The enhancement factors ranged from 2.79 to 4.28, depending on radiation dose, when PG-TXL preceded radiation by 23 h. The enhancement factor derived from radiation close-response curves was as high as 5.13. The radiosensitizing effect of PG-TXL was also dependent on the interval between PG-TXL administration and radiation delivery, with greater enhancement been observed when the interval was decreased. The percentage of G2/M cells was significantly increased to 21.4% 38 h after PG-TXL but declined to a preinjection level of 14.8% 72 h after PG-TXL. PG-T,YL only moderately increased the tumor vascular volume by 37% 24 h after PG-TXL administration,Conclusion: PG-TXL markedly potentiated response of OCa-1 tumor to radiation. When compared to literature data obtained from the same tumor model used here, PG-TXL exhibited stronger radiosensitization effect than TXL, Although its action is possibly mediated by arrest of cells in G2/M phases of cell cycle and by increased turner blood supply, PG-TXL may exert its radiopotentiation activity through increased tumor uptake of PC-TILL and sustained release of TXL in the tumor, Our results show that conjugation of TXL to a polymer has the potential to further enhance its radiosensitizing activity and that clinical trials of PG-TXL in combination with radiation is warranted, (C) 2000 Elsevier Science Inc.