Abstract
Antifolates have been used to treat cancer for the last 50 years and remain the mainstay of many therapeutic regimes. Nucleoside salvage, which depends on plasma membrane transport, can compromise the activity of antifolates. The cardiovascular drug dipyridamole inhibits nucleoside transport and enhances antifolate cytotoxicity in vitro, but its clinical activity is compromised by binding to the plasma protein alpha(1)-acid glycoprotein (AGP). We report the development of a novel pyrimidopyrimidine analogue of dipyridamole, NU3153, which has equivalent potency to dipyridamole, remains active in the presence of physiologic levels of AGP, inhibits thymidine incorporation into DNA, and prevents thymidine and hypoxanthine rescue from the multitargeted antifolate, pemetrexed. Pharmacokinetic evaluation of NU3153 suggested that a soluble prodrug would improve the in vivo activity. The valine prodrug of NU3153, NU3166, rapidly broke down to NU3153 in vitro and in vivo. Plasma NU3153 concentrations commensurate with rescue inhibition in vitro were maintained for at least 16 hours following administration of NU3166 to mice at 120 mg/kg. However, maximum inhibition of thymidine incorporation into tumors was only 50%, which was insufficient to enhance pemetrexed antitumor activity in vivo. Comparison with the cell-based studies revealed that pemetrexed enhancement requires substantial (> or =90%) and durable inhibition of nucleoside transport. In conclusion, we have developed non-AGP binding nucleoside transport inhibitors. Pharmacologically active concentrations of the inhibitors can be achieved in vivo using prodrug approaches, but greater potency is required to evaluate inhibition of nucleoside rescue as a therapeutic maneuver.
Highlights
Antimetabolites were the first rationally designed anticancer drugs and still represent a major class with wide therapeutic applications today
The thymidylate synthase inhibitor AG337 was more active against xenografts deficient in thymidine kinase (TK) than in tumors expressing this enzyme [4]
Whereas the potency of dipyridamole was reduced by 66% in the presence of physiologically relevant concentrations of acid glycoprotein (AGP), AGP had no significant effect on the potency of the novel inhibitors (Fig. 2A)
Summary
Antimetabolites were the first rationally designed anticancer drugs and still represent a major class with wide therapeutic applications today. Salvage of extracellular purine or pyrimidine nucleosides or bases constitutes an intrinsic resistance mechanism to antimetabolite inhibitors of de novo purine or pyrimidine biosynthesis. There is good evidence that the activities of salvage enzymes in cancer cells are higher than those of de novo synthesis [2]. Resistance to antimetabolites by virtue of the activity of salvage pathways increases in parallel with malignancy [3]. Several preclinical studies show that nucleoside and nucleobase salvage by thymidine kinase (TK) and hypoxanthine-guanine phosphoribosyltransferase compromises the antitumor activity of antifolates. Whereas pemetrexed had only modest activity against parental GC3 xenografts at the maximum tolerated dose, it caused marked regressions of GC3 TK-deficient xenografts [6]
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