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  • Title: [The metabolism of high-molecular-weight substances in cells and the effect of anticancer drugs].
    Author: Kanamaru R, Kakuta H, Sato T, Ishioka C, Konishi Y, Wakui A, Dei T.
    Journal: Gan To Kagaku Ryoho; 1987 Mar; 14(3 Pt 2):837-44. PubMed ID: 3566294.
    Abstract:
    The term "high molecular weight substances" used in this paper implies mostly nucleic acids of certain molecular weight and protein, and the genetic aspects of anti-cancer chemotherapy were discussed. Studies on the mechanism of action of 5-FU have been focused on the inhibition of DNA synthesis, and it has been reported that 5-FU inhibits the growth of thymidylate synthesis deleted FM3A Thy 21 cells even in the presence of thymidine, and that the level of TTP is equal to that in control cells. On the other hand, the active metabolite of 5-FU, FdUMP, is known to bind to synthesized thymidylate and 5, 10-methylene-tetrahydrofolic acid to form a ternary complex. Recently, the cytocidal effect of 5-FU was observed in thymidylate synthetase-deficient cells in the presence of a sufficient amount of thymidine, suggesting that the cytocidal effect of 5-FU might be caused by inhibition of the RNA pathway. In this laboratory, the effect of 5-FU on polysomal patterns and the incorporation of 3H-UR into polysomes was studied in L1210 cells, but no significant difference was observed between normal and 5-FU-treated cells. Ribosomal RNA extracted from the polysomes of 5-FU treated cells appeared to contain a smaller 28S rRNA in comparison to 18S rRNA, indicating that the processing might be inhibited. Expression of mouse H-2Dd mRNA was not influenced by 5-FU at 10(-5) M up to 6 h. Methotrexate (MTX) has a chemical structure similar to folic acid, and is known to bind to DHFR (dihydrofolate reductase), and inhibit the synthesis of TMP. The cellular PRPP content is known to be increased by MTX, which inhibits purine synthesis. The level of PRPP content was found to be increased approximately 25 fold at 3 h after 10(-6) M MTX although normal bone marrow cells showed no increase even after MTX. This increased level of PRPP thus obtained in cancer cells was thought to be used for the phosphorylation of 5-FU. Clinically, sequential chemotherapy using MTX and 5-FU was employed successfully for solid tumors on the basis of the experimental evidence. In order to minimize the adverse effects of anti-cancer drugs, a technique involving the incorporation of the drug-resistant gene into normal bone marrow cells has been designed in this laboratory, and the MTX-resistant cells thus obtained are transplanted into the tumor-bearing mice.
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