Pyrimidine Metabolism in Man. V. The Measurement in Vivo of the Biochemical Effect of Antineoplastic Agents in Animal and Human Subjects*

Abstract

Many in v'ivo studies have been carried out on purine metabolism in man because of the presence of a readily available end product, uric acid. In the absence of a comparable unique end product, no previous over-all measurements of pyrimidine metabolism in the intact organism have been reported. Studies have been limited to the excretion of /8-aminoisobutyric acid, as a metabolite of thymine (1), the incorporation of pyrimidine precursors into circulating leukocytes (2), the induced urinary excretion of orotic acid and orotidine (3), and the spontaneous urinary excretion of certain trace pyrimidines (4). In this report a method is described for evaluating pyrimidine nucleotide synthesis in the intact organism, based on the release of carbon dioxide-C14 from carboxyl-labeled pyrimidine precursors. The usefulness of this procedure in defining the onset, degree, and duration of action of certain antimetabolites is illustrated by studies in rats, and in patients with leukemia. MATERIALS AND METHODSIntravenous injections of labeled compounds were given through indwelling jugular vein catheters to male albino rats, weighing 125 to 150 g. For collection of expired C1402, air was flushed through a closed metabolic chamber and the carbon dioxide trapped in 3 N NaOH. Acidification of aliquots of this solution allowed trapping of the carbon dioxide in Hyamine base and counting in a Packard Tri-Carb liquid scintillation spectrometer at an efficiency of approximately 45 per cent. Indwelling cystostomy catheters were operatively placed in rats for urinary studies. Sedation with perphenazine (Trilafon, Schering), and hydration with normal or hypotonic saline *

Urinary polypeptides related to collagen synthesis

“…Samples of plasma were deproteinated with 5% trichloroacetic acid (final concentration), centrifuged, and assayed by counting aliquot portions, of the supernatant solution. Total expired air was collected for precisely measured intervals, and estimations of the 'CO2 evolved were made using the method of Rabkin, Frederick, Lotz, and Smith (29).…”

Comparison of carbon-sulfur and carbon-amine bond in therapeutic drug: 4β-S-aromatic heterocyclic podophyllum derivatives display antitumor activity

“…Sampath Kumar 15 designed in silico and prepared a series of 4β-[(4-alkyl)-1, 2, 3-triazol-1-yl] podophyllotoxin derivatives, which proved to be more potent than etoposide and exhibited significant anti-tumor activity with IC 50 values in the range of 0.001–1 μM. Purine analogues have been shown to damage the integrity of DNA and to kill cells as effectively as pyrimidine substituents 16 17 . Thus, naphthalene or benzothiazole cores might have similar bioactivity.…”

The Effect of 6-Azauridine Administration on De Novo Pyrimidine Production in Chronic Myelogenous Leukemia*

“…In animal and human studies the prior administration of AzUR markedly reduced the release of respiratory carbon dioxide-C14 from intravenously administered OA-carboxyl C14 (12,13). This has been presented as evidence for a prompt whole body inhibition of orotidylic acid decarboxylation produced by AzUR.…”