Thymidine phosphorylase moderates thymidine-dependent rescue after exposure to the thymidylate synthase inhibitor ZD1694 (Tomudex) in vitro.
The inhibition of de novo thymidine (dThd) synthesis by the novel folate-based thymidylate synthase (TS) inhibitor ZD1694 (Tomudex) can achieve tumor cell-specific cytotoxicity in vivo. However, nucleosides in the surrounding microenvironment of tumors may be used by the salvage pathway to regenerate any depleted pools, thus providing an efficient mechanism through which to circumvent the ZD1694-dependent toxicity. Anabolism of dThd to dTMP by dThd kinase (TK) is the first committed step in the dThd salvage pathway. However, dThd phosphorylase (dThdPase) can compete with TK by catalyzing the reversible phosphorolytic cleavage of dThd to thymine and deoxyribose 1-phosphate and rendering the salvaged dThd metabolically unavailable. Both TK and dThdPase are up-regulated in some tumors, and their relative importance is not fully defined. We have studied the influence of dThdPase expression on the capacity of exogenous dThd to reverse ZD1694-dependent growth inhibition and have shown that both intra- and extracellular dThdPase activity can effectively moderate dThd-rescue. This suggests that tumor levels of dThdPase may be an important factor in the outcome of ZD1694 therapy.
Patterson
A V
AV
Experimental Oncology Group, Department of Pharmacy, University of Manchester, United Kingdom.
Talbot
D C
DC
Stratford
I J
IJ
Harris
A L
AL
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013936:Thymidine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013940:Thymidylate Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D017077:Culture Media, Conditioned; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; C068874:raltitrexed; D013936:Thymidine