Modulation of thymidine kinase activity: a biochemical strategy to enhance the activation of antineoplastic drugs.
Thymidine kinase is a key enzyme responsible for the activation of several anticancer and antiviral drugs. As the first enzyme in the salvage pathway of thymidine, it is regulated by the feedback inhibition exerted by the end-product of the pathway, namely thymidine 5'-triphosphate. 5'-Aminothymidine is a non-toxic analogue of thymidine capable of interfering with this regulatory mechanism. In fact, it has been shown that 5'-aminothymidine increases the cytotoxicity and metabolism of various thymidine analogues currently in use of the clinic as antineoplastic agents. This mini-review article focuses in the evidence supporting the role of 5'-aminothymidine as a potential prototype drug for a new class of anticancer agents: drugs which affect the regulation of key metabolic pathways that determine the efficacy of agents with cytotoxic activity. The mechanism of action, antineoplastic activities and basis for selectivity in tissue culture models are also described.
Vázquez-Padua
M A
MA
Department of Pharmacology, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico 00960-6037.
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000998:Antiviral Agents / Q000493:pharmacokinetics; D001711:Biotransformation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004249:DNA Damage / Q000528:radiation effects; D015195:Drug Design; D005246:Feedback / Q000187:drug effects; D005467:Floxuridine / Q000493:pharmacokinetics; D006367:HeLa Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007065:Idoxuridine / Q000493:pharmacokinetics / Q000633:toxicity; D009363:Neoplasm Proteins / Q000378:metabolism; D009711:Nucleotides / Q000037:antagonists & inhibitors; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D001743:Urinary Bladder / Q000201:enzymology; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000473:pathology; D014709:Vero Cells / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009363:Neoplasm Proteins; D009711:Nucleotides; D011838:Radiation-Sensitizing Agents; D005467:Floxuridine; C023821:5-(aminomethyl)-2'-deoxyuridine; D013937:Thymidine Kinase; D007065:Idoxuridine; D013936:Thymidine