The molecular targets of antitumor 2'-deoxycytidine analogues.
Most antitumor 2'-deoxycytidine (dCyd) analogues, such as Ara-C (1-beta-arabinofuranosylcytosine) and gemcitabine (2'-deoxy-2',2'-difluolo-cytidine), have common antitumor mechanisms and metabolic pathways. These nucleosides are transported into tumor cells via specific nucleoside transporters (NT), and then phosphorylated toward each monophosphate form by dCyd kinase. Finally, tri-phosphate forms are enzymatically produced and efficiently inhibit DNA synthesis. It is believed that dCyd kinase is a very important activator of antitumor 2'-dCyd analogues and an attractive molecular target for biochemical modulation. Resistant cells established by continuous exposure to 2'-dCyd analogues in vitro have extremely high resistance as compared with parental cells, and their resistance indexes are sometimes increased between several hundred to thousand times. Such high resistance is generally attributed to deficiency of dCyd kinase activity, but the clinical resistance index of Ara-C-resistant patients is estimated to be increased a maximum of 20 times compared with non-treated patients. The differences between experimental and clinical resistances may be caused by different mechanisms of resistance. To clarify such resistance mechanisms, we carried out research focused on NT and dCyd kinase. Our results show that earlier resistant cells, that exhibited a 20 times lower resistance index, had a reduced NT activity but retained dCyd kinase activity. In contrast, dCyd kinase activity was deficient in later resistant cells that showed maximum resistance. Both NT and dCyd kinase activities are important for the acquisition of resistance and are useful as molecular targets for biochemical modulation or the development of novel antitumor 2'-dCyd analogues. These results suggest that NT activity is likely to be responsible for clinical resistance.
Obata
Tohru
T
Department of Experimental Therapeutics, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan. tobata@kenroku.kanazawa-u.ac.jp
Endo
Yoshio
Y
Murata
Daigo
D
Sakamoto
Kazuki
K
Sasaki
Takuma
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase