Bisphosphonates activate the 5-fluorouracil/uracil phosphoribosyltransferase activity present in Saccharomyces cerevisiae cell extracts: implications for tumor treatments.
Most of the effects described for bisphosphonates (pC(R1)(R2)p) are related, directly or indirectly with a pyrophosphate moiety. Bisphosphonates are (i) analogs of pyrophosphate in the synthesis of ATP derivatives (AppC(R1)(R2)p) catalyzed by ligases and (ii) inhibitors of enzymes of the mevalonate pathway with substrates containing a terminal pyrophosphate. Searching for the role of bisphosphonates on other reactions involving pyrophosphate, we explored their effect on a phosphoribosyltransferase activity, present in Saccharomyces cerevisiae cell extracts, using 5-fluorouracil or uracil as substrates. Unexpectedly, bisphosphonates increased the initial rate of synthesis of 5-FUMP (from 5-fluorouracil and phosphoribosylpyrophosphate): etidronate (2.8+/-0.3 times); pamidronate (2.6+/-0.4 times); alendronate (2.5+/-0.6 times) and clodronate (2.0+/-0.1 times). Similar values for the synthesis of UMP (from uracil and phosphoribosylpyrophosphate) were obtained in the presence of bisphosphonates. The values of the activation constants determined for alendronate and clodronate for the synthesis of UMP were 0.05+/-0.02 mM and 0.32+/-0.22 mM, respectively. These results raise the possibility that bisphosphonates enhance the effect of 5-fluorouracil (or other uracil prodrugs) in the treatment of bone tumors or bone tumor metastases.
Pérez-Zúñiga
Francisco J
FJ
Departamento de Bioquímica, Instituto de Investigaciones Biomédicas Alberto Sols UAM/CSIC, Facultad de Medicina, 28029 Madrid, Spain.
Günther Sillero
María A
MA
Sillero
Antonio
A
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D010430:Pentosyltransferases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology; D014498:Uracil / Q000494:pharmacology
D000964:Antimetabolites, Antineoplastic; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D014498:Uracil; D010430:Pentosyltransferases; D005472:Fluorouracil