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.