Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrazofurin (PYF), a C-riboside, inhibited the replication of cultured Novikoff rat hepatoma cells, HeLa cells, and mouse L-cells at concentrations as low as 0.1 to 10 muM, but Novikoff cells were more sensitive than the cells of the other two cell lines. Inhibition of cell replication was completely prevented by the presence of 0.1 to 1 mM uridine in the medium, and partly by the presence of other pyrimidine, but not purine nucleosides. A 2- to 4-hr treatment of the cells with 10 muM PYF resulted in a 2-fold increase in the rate of incorporation of uridine into the acid-soluble pool and nucleic acids, while the rate of incorporation of adenosine into RNA was reduced about 85%. The incorporation of adenosine and deoxyuridine into DNA were reduced about 85 and 50%, respectively. The results are consistent with the view that PYF inhibits the de novo synthesis of pyrimidine nucleosides. The inhibition of cell replication seems to be due mainly to an inhibition of DNA rather than RNA synthesis, resulting from a rapid depletion of the pyrimidine deoxynucleotide pool, since addition of thymidine and deoxycytidine reversed the inhibition of DNA synthesis and cell replication by PYF. PYF must enter the cells to exert its toxicity since the toxicity of PYF was reduced 70 to 80% by the presence of 8 muM Persantin, a potent inhibitor of the facilitated and simple diffusion of various substrates, in the medium. If PYF is incorporated via normal nucleoside salvage pathways, its affinity for the nucleoside transport system(s) and kinases, must be low since, even at a concentration of 1 mM, it had only a slight effect on the initial rates of incorporation of various nucleosides into the nucleotide pool.
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PMID:Inhibition of de novo pyrimidine nucleotide and DNA synthesis and growth of cultured Novikoff rat hepatoma cells and other cell lines by pyrazofurin (NSC 143095). 18 63

Hepatoma 8999 was sensitive to Lycurim [1,4-di-(methylsulfonyloxy-ethylamino)-1,4-dideoxy-ms-erythritol] with a mean lethal dose (LD50) of 8.1 X 10(-8) M for a 6-hour treatment in vitro. The drug dose lethal to 10% of the rats with Lycurim (10 mg/kg) injected ip 12 times into hepatoma 8999-bearing BUF rats at 10-day intervals provided a mean increase in life-span (ILS) of 156%. The more rapidly growing, less differentiated hepatoma 3924A was tenfold less sensitive to Lycurim in vitro, and three treatments in vivo (10 mg/kg given every 8 days) gave an ILS of only 18% in ACI/N rats. Because hepatoma 8999 had a high adenosine kinase activity, the effect of Pyrazofurin (PF; 3-beta-D-ribofuranosyl-4-hydroxypyrazole-5-carboxamide) was examined in vitro: The LD50 was 8.5 X 10(-8) M in a 6-hour exposure. In hepatoma 3924A, with a fifteenfold lower adenosine kinase, the LD50 was 22-fold higher. Three treatments with PF (4 mg/kg given every 2 days) in hepatoma 8999 caused an 18% ILS and no host toxicity, but in hepatoma 3924A no significant ILS was observed. Lycurim combined with PF (0.05 microM each) in hepatoma 8999 cells in vitro provided synergistic kill, but Lycurim and PF (0.3 and 1 microM, respectively) in hepatoma 3924A cells yielded summation. When 10 rats with hepatoma 8999 were treated 15 times with the optimal dose of Lycurim (7.5 mg/kg every 10 1/2 days), 1-year survivors numbered 7. Alternate doses of Lycurim (7.5 mg/kg) and PF (3 mg/kg) at 5-day intervals for 4 months to 10 rats gave an ILS of 152% with eight 1-year survivors and no host toxicity.
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PMID:Rat hepatomas: chemotherapy with lycurim and pyrazofurin. 695 Oct 80