Tumor radiosensitization by sustained intratumoral release of bromodeoxyuridine

We have previously reported that the use of the polymer bis(p-carboxyphenox y)propane-sebacic acid (20:80) for intratumoral delivery of cisplatinum in a mouse tumor model (RIF-1) potentiated the effects of acute and fractionat ed radiation. This mode of drug delivery seems particularly applicable to t he administration of radiosensitizing drugs because an optimum concentratio n of radiosensitizer can be maintained in the tumor over the prolonged peri od required for fractionated radiation treatment. We have now investigated, in the same tumor model, radiosensitization by the thymidine analogue brom odeoxyuridine (BrdUrd). BrdUrd (20%, w/w) was incorporated into bis(p-carboxyphenoxy)propane-sebaci c acid (20:80) and polymer rods containing the drug implanted in the RIF-1 tumor. Preliminary in vitro studies of the rate of release of BrdUrd from t he polymer showed an initial rapid loss over 24 h, followed by a slower rel ease extending over the next 5 days. In experiments in which tumor cells, w hich had incorporated BrdUrd in vivo from implanted polymer, were excised a nd a single cell suspension irradiated in vitro radiosensitization indicati ve of BrdUrd incorporation was associated mainly with an increase in the co nstant for the linear quadratic model of cell survival. Radiosensitization was seen for tumor cells harvested between 5 and 10 days after polymer impl ant, a finding that is consistent with results of experiments in which the percentage of cells that had incorporated BrdUrd were measured by flow cyto metry at various times after polymer/BrdUrd implant. The proportion of tumo r cells positive for BrdUrd was 40-50% between 3 and 8 days after polymer i mplant. When tumors were irradiated in situ and response measured in terms of tumor growth delay (TGD), radiosensitization was not seen for an acute dose of 1 6.5 Gy, In contrast, significant radiosensitization was seen for fractionat ed treatments when polymer/BrdUrd was implanted 3 days before the first rad iation dose. For a dose of 5 x 6 Gy, TGD was increased from 22 days for rad iation alone to 27 days for radiation plus polymer implant. For 10 x 6 Gy f ractions, TGD increased from 45-77 days for those mice in whom the tumor ev entually regrew, whereas for 25% of the mice in this group the tumor volume was reduced to a point where it was no longer detectable and there was no recurrence for at least 120 days after treatment.