Evidence that 5'-deoxy-5-fluorouridine may not be activated by the same mechanism as 5-fluorouracil.
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Biomedical subjects
Publications and source records attributed to G L Carter.
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Combinations of inhibitors directed at the individual components of ribonucleotide reductase were studied for their effects on L1210 cell growth in culture. The combinations included pyrozoloimidazole (IMPY) plus deoxyadenosine and hydroxyurea plus deoxyadenosine. Modulators were utilized to potentiate the effects of hydroxyurea, IMPY, or deoxyadenosine. Desferal was used to modulate the activity of hydroxyurea and IMPY while erythoro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was used as the modulator of deoxyadenosine metabolism. While the combinations of deoxyadenosine-EHNA, hydroxyurea-Desferal, or IMPY-Desferal caused increased growth inhibition of L1210 cells at high drug concentrations, combinations which consisted of deoxyadenosine-EHNA-IMPY-Desferal or deoxyadenosine-EHNA-hydroxyurea-Desferal gave strong synergistic inhibition of L1210 cell growth in culture at concentrations of each of the drugs which alone had minimal inhibitory effects on tumor cell growth. The four-drug combination was clearly more effective than any three-drug combination in terms of inhibition of tumor cell growth. It was also observed that the concentrations of the modulators (Desferal or EHNA) were as critical as the concentrations of hydroxyurea, IMPY, or deoxyadenosine in establishing an effective drug combination.
The resistance of a Novikoff hepatoma cell line (N1-S1/FdUrd) to 5-fluorouracil (FUra) was reversed by the inclusion of inosine in the culture medium. As the concentration of inosine in the medium was increased, there was a marked increase in the uptake of [14C]FUra and conversion to nucleotides with a corresponding increase in the incorporation into RNA. While FUra alone had no effect on this resistant cell line, the combination of FUra plus inosine altered the levels of ribose 1-phosphate but not 5-phosphoribosyl 1-pyrophosphate, altered the maturation of precursor ribosomal RNA by blocking the formation of 18S RNA, altered the methylation of the ribosomal RNA, and caused inhibition of the growth of these cells. No evidence was obtained that fluorodeoxyuridine 5'-monophosphate was formed in the N1-S1/FdUrd cells as a result of treatment with FUra plus inosine. In addition, the metabolism of [3H]deoxycytidine in the presence of FUra plus inosine in the intact N1-S1/FdUrd cells did not indicate significant inhibition of thymidylate synthetase as evidenced by the levels of deoxyuridine 5'-monophosphate or conversion to thymidine 5'-monophosphate.
Postiive end-expiratory pressure (PEEP), in combination with mechanical ventilation, is efficacious in the treatment of some forms of adult respiratory insufficiency. PEEP in excess of 10 to 15 torr usually is not recommended; however, higher levels of PEEP may be required to reverse the pulmonary venous admixture. The efficacy of optimizing cardiopulmonary function with varying levels of PEEP is described.
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