Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy.
For decades it has been well known that elevated levels of homocysteine are harmful to humans on the basis of clinical observations derived from classical model diseases, such as inherited metabolic disorders. This group of diseases includes classical homocystinuria and several other inherited diseases affecting the so-called 'transsulfuration pathways'. Homocysteine lies in a metabolic checkpoint that interconnects one-carbon-transferring reactions with metabolism of sulfur-containing amino acids, since every molecule of 5-methyltetrahydrofolate derived either from plasma or generated from other folate species must be demethylated to liberate the reduced tetrahydrofolate. This unidirectional mechanism operates in every cell and has no alternative in eukaryotic cells. Antifolates are a group of anticancer agents targeting various metabolic steps within folate metabolism. They exert an indirect influence on the rate of appearance/disappearance of homocysteine from cellular and plasma compartments. Recently, it has been postulated that homocysteine may be a marker of the 'pharmacodynamic effect' of methotrexate, but studies attesting to this role are only now emerging. Here, we explore the genetic disease of folate and homocysteine metabolism and discuss the links between these model disorders with pharmacology and pharmacogenetics of folate antagonists used in the clinic. We outline possible ways of how homocysteine may be used as a biomarker of antifolate therapy.
Valik
Dalibor
D
Department of Laboratory Medicine, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic. valik@mou.cz
Radina
Martin
M
Sterba
Jaroslav
J
Vojtesek
Borivoj
B
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D015415:Biomarkers; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy*
D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D005493:Folic Acid Antagonists; D006710:Homocysteine; D008727:Methotrexate