Inhibition of phosphoribosylpyrophosphate synthetase by 4-methoxy-(MRPP) and 4-amino-8-(D-ribofuranosylamino) pyrimido[5,4-d]pyrimidine (ARPP).
The basis for the antitumor activities of the exocyclic amino nucleosides 4-amino-(ARPP) and 4-methoxy-8-(D-ribofuranosylamino)pyrimido[5,4-d]pyrimidine (MRPP) was investigated. The primary target of these nucleosides appeared to be 5-phospho-alpha-D-ribofuranose-1-pyrophosphate (PRPP) synthetase. MRPP-5'-monophosphate was a competitive inhibitor (Ki = 40 microM) of the activation of this enzyme by the cofactor inorganic phosphate (K alpha = 2.2 mM). Consequently, ARPP and MRPP treatment of WI-L2 cultures rapidly inhibited both de novo pyrimidine and purine synthesis as well as the nucleotide salvage reactions dependent on PRPP, ARPP or MRPP treatment completely prevented [14C]bicarbonate incorporation into acid-soluble pyrimidine and purine nucleotides. The rate of salvage of [8-14C]hypoxanthine to form IMP was decreased by 85%. Treatment of cells with these agents caused a 50% reduction in the steady-state level of PRPP. When the capacity of the treated cells for sustained synthesis of PRPP was examined by adenine incorporation, the rate of adenine uptake was inhibited by greater than 50%. In vivo treatment of BDF1 mice with a single dose of ARPP (173 mg/kg) or MRPP (62 mg/kg) extended the mean life span of the mice, which had been inoculated intraperitoneally 1 day earlier with 1 x 10(6) L1210 murine leukemia cells, by 62 and 82% respectively. These studies indicate that MRPP and ARPP inhibit PRPP synthetase, and that PRPP synthetase may be a viable target in the development of certain antitumor agents.
Nord
L D
LD
Department of Biochemistry, ICN Nucleic Acid Research Institute, Costa Mesa, CA 92626.
Willis
R C
RC
Breen
T S
TS
Avery
T L
TL
Finch
R A
RA
Sanghvi
Y S
YS
Revankar
G R
GR
Robins
R K
RK
D000243:Adenosine Deaminase / Q000494:pharmacology; D000248:Adenosine Kinase / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D051379:Mice; D009243:NAD / Q000378:metabolism; D009711:Nucleotides / Q000096:biosynthesis; D010754:Phosphoribosyl Pyrophosphate / Q000032:analysis / Q000096:biosynthesis; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C011650:NSC 283867; D009711:Nucleotides; D011741:Pyrimidine Nucleosides; D009243:NAD; C061494:4-methoxy-8-(ribofuranosylamino)pyrimido(5,4-d)pyrimidine; D010754:Phosphoribosyl Pyrophosphate; D010770:Phosphotransferases; D000248:Adenosine Kinase; D012268:Ribose-Phosphate Pyrophosphokinase; D000243:Adenosine Deaminase