Preclinical evaluation of a novel pyrimidopyrimidine for the prevention of nucleoside and nucleobase reversal of antifolate cytotoxicity.
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.
Thomas
Huw D
HD
Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Saravanan
Kappusamy
K
Wang
Lan-Zhen
LZ
Lin
Mei-Ju
MJ
Northen
Julian S
JS
Barlow
Hannah
H
Barton
Marion
M
Newell
David R
DR
Griffin
Roger J
RJ
Golding
Bernard T
BT
Curtin
Nicola J
NJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004176:Dipyridamole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009705:Nucleosides / Q000378:metabolism*; D009961:Orosomucoid / Q000378:metabolism; D000068437:Pemetrexed; D010766:Phosphorylation / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; C544310:NU 3153; D009705:Nucleosides; D009961:Orosomucoid; D011355:Prodrugs; D000068437:Pemetrexed; D006147:Guanine; D004176:Dipyridamole; D013940:Thymidylate Synthase; D013936:Thymidine