Nucleoside transport inhibitors, dipyridamole and p-nitrobenzylthioinosine, selectively potentiate the antitumor activity of NB1011.
NB1011, a novel anticancer agent, targets tumor cells expressing high levels of thymidylate synthase (TS). NB1011 is converted intracellularly to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate, deoxyuridine monophosphate, for binding to TS. Unlike inhibitors, NB1011 becomes a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic product(s). In vitro cytotoxicity studies demonstrate NB1011's preferential activity against tumor cells expressing elevated TS protein levels. Additionally, NB1011 has antitumor activity in vivo. To identify drugs which interact synergistically with NB1011, we screened 13 combinations of chemotherapeutic agents with NB1011 in human tumor and normal cells. Dipyridamole and p-nitrobenzylthioinosine (NBMPR), potent inhibitors of equilibrative nucleoside transport, synergized with NB1011 selectively against 5-fluorouracil (5-FU)-resistant H630R10 colon carcinoma cells [combination index (CI)=0.75 and 0.35] and Tomudex-resistant MCF7TDX breast carcinoma cells (CI=0.51 and 0.57), both TS overexpressing cell lines. These agents produced no synergy with NB1011 in Det551 and CCD18co normal cells (CI > 1.1) lacking TS overexpression. Dipyridamole potentiated NB1011's cytotoxicity in medium lacking nucleosides and bases, suggesting a non-salvage-dependent mechanism. We demonstrate that nucleoside transport inhibitors, dipyridamole and NBMPR, show promise for clinically efficacious combination with NB1011.
Boyer
Christopher R
CR
NewBiotics, Inc, San Diego, CA 92121, USA.
Karjian
Patricia L
PL
Wahl
Geoffrey M
GM
Pegram
Mark
M
Neuteboom
Saskia T C
ST
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004176:Dipyridamole / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D033703:Nucleoside Transport Proteins; D011799:Quinazolines / Q000494:pharmacology; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; C421011:NB1011; D033703:Nucleoside Transport Proteins; D011799:Quinazolines; D013876:Thiophenes; D013868:Thioinosine; D004176:Dipyridamole; D013940:Thymidylate Synthase; C068874:raltitrexed; D001973:Bromodeoxyuridine; C001789:4-nitrobenzylthioinosine; D005472:Fluorouracil