We have previously reported that the use of the
polymer bis(p-carboxyphenoxy)
propane-
sebacic acid (20:80) for intratumoral delivery of
cis-platinum in a mouse
tumor model (RIF-1) potentiated the effects of acute and fractionated radiation. This mode of
drug delivery seems particularly applicable to the administration of
radiosensitizing drugs because an optimum concentration of radiosensitizer can be maintained in the
tumor over the prolonged period required for fractionated
radiation treatment. We have now investigated, in the same
tumor model, radiosensitization by the
thymidine analogue
bromodeoxyuridine (BrdUrd). BrdUrd (20%, w/w) was incorporated into bis(p-carboxyphenoxy)
propane-
sebacic 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 the
polymer showed an initial rapid loss over 24 h, followed by a slower release extending over the next 5 days. In experiments in which
tumor cells, which had incorporated BrdUrd in vivo from implanted
polymer, were excised and a single cell
suspension irradiated in vitro radiosensitization indicative of BrdUrd incorporation was associated mainly with an increase in the alpha constant for the linear quadratic model of cell survival. Radiosensitization was seen for
tumor cells harvested between 5 and 10 days after
polymer implant, a finding that is consistent with results of experiments in which the percentage of cells that had incorporated BrdUrd were measured by flow cytometry at various times after
polymer/BrdUrd implant. The proportion of
tumor cells positive for BrdUrd was 40-50% between 3 and 8 days after
polymer implant. 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 16.5 Gy. In contrast, significant radiosensitization was seen for fractionated treatments when
polymer/BrdUrd was implanted 3 days before the first radiation dose. For a dose of 5 x 6 Gy, TGD was increased from 22 days for radiation alone to 27 days for radiation plus
polymer implant. For 10 x 6 Gy fractions, TGD increased from 45-77 days for those mice in whom the
tumor eventually 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.