Yuan X, Dillehay L E, Williams J R, Shastri V R, Williams J A
Radiobiology Laboratory, Division of Radiation Oncology, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Int J Cancer. 2001 Apr 20;96(2):118-25. doi: 10.1002/ijc.1005.
Local polymeric delivery enhances IUdR radiosensitization of human malignant gliomas (MG). The combined low-dose rate (LDR) (0.03 Gy/h) and fractionated high-dose rate (HDR) treatments result in cures of experimental MGs. To enhance efficacy, we combined polymeric IUdR delivery, LDR, and HDR for treatments of both subcutaneous and intracranial MGs. In vitro: Cells (U251 MG) were trypsinized and replated in triplicate 1 day prior to LDR irradiation in media either without (control) or with 10 microM IUdR. After 72 hr, LDR irradiation cells were acutely irradiated (1.1 Gy/min) with increasing (0, 1.25, 2.5, 5.0, or 10 Gy) single doses. Implantable IUdR polymers [(poly(bis(p-carboxyphenoxy)-propane) (PCPP): sebaic acid (PCPP:SA), 20:80] (50% loading; 10 mg) were synthesized. In vivo: For flank vs. intracranial tumors, mice had 6 x 10(6) subcutaneous vs. 2 x 10(5) intracranial cells. For intracranial or subcutaneous MGs, mice had intratumoral blank (empty) vs. IUdR polymer treatments. One day after implantation, mice had immediate external LDR (3 cGy/h x 3 days total body irradiation) or HDR (2 Gy BID x 4 days to tumor site) or concurrent treatments. For the in vitro IUdR treatments, LDR resulted in a striking increase in cell-killing when combined with HDR. For the in vivo LDR treatments of flank tumors, the growth delay was greater for the IUdR vs. blank polymer treatments. For the combined LDR and HDR, the IUdR treatments resulted in a dramatic decrease in tumor volumes. On day 60 the log V/V0 were -1.7 +/- 0.22 for combined LDR + HDR + IUdR polymer (P < 0.05 vs. combined LDR + HDR + blank polymer). Survival for the intracranial controls was 22.9 +/- 1.2 days. For the blank polymer + LDR vs. blank polymer + LDR + HDR treatments, survival was 25.3 +/- 1.7 (P = NS) vs. 48.1 +/- 3.5 days (P < 0.05). For IUdR polymer + LDR treatment survival was 27.3 +/- 2.3 days (P = NS). The most striking improvement in survival followed the IUdR polymer + LDR + HDR treatment: 66.0 + 6.4 days (P < 0.05 vs. blank polymer + LDR + HDR). The polymeric IUdR delivery plus combined continuous LDR and HDR treatments results in growth delay and improved survival in animals bearing the MG xenografts. This treatment may hold promise for the treatment of human MGs.
局部聚合物给药可增强碘苷（IUdR）对人类恶性胶质瘤（MG）的放射增敏作用。低剂量率（LDR）（0.03 Gy/h）与分次高剂量率（HDR）联合治疗可治愈实验性MG。为提高疗效，我们将聚合物IUdR给药、LDR和HDR联合用于皮下和颅内MG的治疗。体外实验：在LDR照射前1天，将细胞（U251 MG）用胰蛋白酶消化并一式三份重新接种于不含（对照）或含有10 microM IUdR的培养基中。72小时后，对接受LDR照射的细胞进行急性照射（1.1 Gy/min），单次剂量递增（0、1.25、2.5、5.0或10 Gy）。合成了可植入的IUdR聚合物[聚（双（对羧基苯氧基）丙烷）（PCPP）：癸二酸（PCPP:SA），20:80]（载药量50%；10 mg）。体内实验：对于侧腹肿瘤与颅内肿瘤，小鼠分别接种6×10⁶皮下细胞与2×10⁵颅内细胞。对于颅内或皮下MG，小鼠接受瘤内空白（空）聚合物或IUdR聚合物治疗。植入后1天，小鼠接受即刻体外LDR（3 cGy/h×3天全身照射）或HDR（2 Gy，每日两次×4天至肿瘤部位）或联合治疗。对于体外IUdR治疗，LDR与HDR联合时细胞杀伤作用显著增强。对于侧腹肿瘤的体内LDR治疗，与空白聚合物治疗相比，IUdR治疗的生长延迟更大。对于LDR和HDR联合治疗，IUdR治疗导致肿瘤体积显著减小。在第60天，联合LDR + HDR + IUdR聚合物组的log V/V0为-1.7±0.22（与联合LDR + HDR +空白聚合物组相比，P < 0.05）。颅内对照组的生存期为22.9±1.2天。对于空白聚合物 + LDR与空白聚合物 + LDR + HDR治疗，生存期分别为25.3±1.7天（P =无显著性差异）与48.1±3.5天（P < 0.05）。对于IUdR聚合物 + LDR治疗，生存期为27.3±2.3天（P =无显著性差异）。生存期改善最显著的是IUdR聚合物 + LDR + HDR治疗：66.0 + 6.4天（与空白聚合物 + LDR + HDR相比，P < 0.05）。聚合物IUdR给药加上连续LDR和HDR联合治疗可导致携带MG异种移植物的动物生长延迟并提高生存期。这种治疗方法可能对人类MG的治疗具有前景。
