Enzymic programs of rat bone marrow and the impact of acivicin and tiazofurin.
The in vivo actions of two antimetabolites, acivicin (NSC-163501) and tiazofurin (NSC-286193), were examined on the enzymic programs of rat bone marrow. From the bone marrow of the femurs, 100,000 g supernatant fractions were prepared; enzymic activities were measured by isotopic assays, and cellularity was determined. In the normal bone marrow, the specific activities of pyrimidine de novo synthetic enzymes, CDP reductase, dTMP synthase, CTP synthase, carbamoyl-phosphate synthase II (synthase II), orotidine 5'-phosphate decarboxylase and aspartate carbamoyltransferase, were 1, 2.7, 5, 10, 63 and 601 nmol/hr/mg protein, respectively, whereas those of the salvage enzymes, deoxycytidine, thymidine, cytidine and uridine kinases were 3, 43, 149, and 367 nmol/hr/mg protein, respectively. In purine biosynthesis, the activities of the de novo synthetic enzymes, IMP dehydrogenase, formylglycinamidine ribonucleotide (FGAM) synthase, GMP synthase, amidophosphoribosyl-transferase (AT) and adenylosuccinate synthase were 16, 8, 107, 78 and 124 nmol/hr/mg protein, respectively, and those of the salvage enzymes, adenine, hypoxanthine and guanine phosphoribosyl-transferases, were 340, 407, and 1018 nmol/hr/mg protein, respectively. The sequence of events was elucidated after a single i.p. injection of acivicin (5 mg/kg) or tiazofurin (200 mg/kg). Within 2 hr after acivicin injection, CTP, GMP and FGAM synthases lost 85-90%, while AT and synthase II lost 50 and 80%, respectively, of their activities. The activities rose to near normal range by 72-96 hr. The bone marrow cellularity decreased, reaching a nadir at 24 and 48 hr, and returning to normal range by 72 and 92 hr; thymidine kinase activity followed a similar pattern. Tiazofurin injection depressed IMP dehydrogenase activity to 20% by 2 hr with a rebound to normal range by 48 and 72 hr. The cellularity decreased more slowly, reaching its lowest point at 24 hr and returning to normal range at 72 hr. For acivicin the marked depletion of the activities of the glutamine-utilizing enzymes and for tiazofurin that of IMP dehydrogenase might account, in part at least, for the bone marrow toxicity of these antimetabolites. Because of the presence in the bone marrow of high activities of purine and pyrimidine salvage enzymes, it should be possible to design methods utilizing nucleosides and nucleobases to protect the bone marrow from the action of antimetabolites.
Prajda
N
N
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46223.
Natsumeda
Y
Y
Ikegami
T
T
Reardon
M A
MA
Szondy
S
S
Hashimoto
Y
Y
Emrani
J
J
Weber
G
G
D000818:Animals; D001221:Aspartate Carbamoyltransferase / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology*; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases; D003842:Deoxycytidine Kinase / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008025:Ligases / Q000378:metabolism; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000378:metabolism
D007555:Isoxazoles; D010080:Oxazoles; D012263:Ribonucleosides; D013938:Thymidine Monophosphate; D012254:Ribavirin; C019857:CDP reductase; D012262:Ribonucleoside Diphosphate Reductase; D013940:Thymidylate Synthase; D001221:Aspartate Carbamoyltransferase; D003842:Deoxycytidine Kinase; D009964:Orotidine-5'-Phosphate Decarboxylase; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C006303:acivicin; C033706:tiazofurin