Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Pyrimidine Analogues:

    • Antimetabolites include pyrimidine analogs which inhibit both DNA and RNA function.¹ 

      • These agents inhibit synthesis of DNA precursors and by group include the fluoropyrimidines and certain purine analogs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG).

        • Other analogs including cytidine and adenosine nucleoside analogues are incorporated into DNA but block elongation and function.

      • DNA consists of four bases, two pyrimidines consisting either of thymine and cytosine and two purines, guanine and adenine.

        • In the case of RNA, uracil substitutes for thiamine as a base.

        • The antineoplastic effects of pyrimidine analogs is based on the idea that the precursors first enter the tumor cells and then are activated later to cytoxic forms which inhibit DNA synthesis.¹

          • One example uses a well-known antineoplastic drug 5-fluorouracil (5-FU).

          • The initial step involves conversion of the 5-FU analog to an FdUMP (5-fluoro-2'-deoxyuridine 5'-monophosphate).

          • FdUMP inhibits thymidylate synthase, enzyme required to catalyze the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP).¹

      • 5-FU Metabolism⁷

        "The 5-flourouracil (5-FU) metabolism pathway. "In tumor cells 5-FU is converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP) by the action of orotate phosphoribosyltransferase. "5-FdUMP inhibits the DNA synthesis by competing with deoxyuridine monophosphate (dUMP) for binding to thymidylate synthase in a complex that is stabilized by the reduced folate 5, 10-methylene tetrahydrofolate. "5-FU can also inhibit RNA synthesis and a pathway that involves us metabolism by orotate phosphoribosyltransferase to 5-fluorouridine monophosphate (5-FUMP) and subsequent conversion to 5-fluorouridine trisphosphate (5-FUTP) via 5-fluorouridine diphosphate (5-FUDP). Extracellular catabolism of 5-FU by dihydropyrimidine dehydrogenase reduces the level of 5-FU for the uptake into the tumor cells."

       

      • Modifications of naturally occurring base and deoxyribonucleoside analogues

      • Cytosine and Cytidine (left) and Capecitabine (right, Xeloda), a Cytosine Anticancer Analogue

        Cytosine(top) and Cytidine (bottom) Cytidine is the pyrimidine nucleoside consisting of the base cytosine linked to the 5-carbon suger D-ribose.	Capecitabine (Xeloda)

         

      • Cytosine and Cytidine (left) and 5-Azacitidine (right, Vidaza), a Cytosine Anticancer Analogue

        Cytosine(top) and Cytidine (bottom) Cytidine is the pyrimidine nucleoside consisting of the base cytosine linked to the 5-carbon suger D-ribose.	5-Azacytidine (Vidaza)