Cancer research
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The irregular nature of solid tumor vasculature produces a heterogeneous distribution of antibody-targeted therapies within the tumor mass, which frequently results in reduced therapeutic efficacy. We have, therefore, combined two complementary therapies: Antibody-directed Enzyme Prodrug Therapy (ADEPT), which targets tumor cells, and an agent that selectively destroys tumor vasculature. A single i.p. dose (27.5 mg/kg) of the drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), given to nude mice bearing the LS174T colorectal xenograft, destroyed all but a peripheral rim of tumor cells, without enhancing survival. ⋯ This correlated with the time of vascular shut-down induced by the antivascular agent. We are currently investigating whether it is more advantageous to trap increased levels of conjugate or prodrug within the tumor for maximal enhancement of conventional ADEPT. These studies demonstrate that combined use of antibody-directed and antivascular therapies can significantly benefit the therapeutic outcome of either strategy alone.
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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). ⋯ 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.