Metabolites of tiazofurin as mediators of its biochemical and pharmacologic effects
Tiazofurin (2-β-D-ribofuranosylthiazole-4-carboxamide) was synthesized by the medicinal chemists at ICN as one of a series of potential antiviral compounds [1,2]. In fact, the agent does exhibit a modest to moderate degree of activity against several pathogenic viruses [2,3]. However, at the time, this activity apparently was not judged sufficient to warrant development of the drug towards clinical trials. With the advent of managerial changes at ICN, Dr. Kenneth Paull of the National Cancer Institute made arrangements with Dr. Roland Robins, the chemist who had designed tiazofurin, to screen that compound and a number of related nucleosides for antineoplastic activity. These studies revealed that tiazofurin was effective against the L1210 and P388 leukemias and prompted a broader examination of the compound’s oncolytic potential. Surprisingly, tiazofurin proved to be effective against the subcutaneous Lewis lung carcinoma, a transplantable tumor resistant to the vast majority of standard and experimental chemotherapeutic drugs. Moreover, cures were achieved over a broad range of doses of the compound . It was these studies, then, that prompted the development of tiazofurin toward clinical trials as an antitumor drug.
KeywordsNucleoside Diphosphate Kinase Acetate Kinase Adenosine Kinase P388 Leukemia Fast Atom Bombardment Mass Spectrum
Unable to display preview. Download preview PDF.
- 8.Jayaram HN, Smith AL, Glazer RI, Johns DG, and Cooney DA: Studies on the mechanism of action of 2-(β-D-ribofuranosylthiazole-4-carboxamide (NSC 286193)-II. Relationship between dose level and biochemical effects in P388 leukemia in vivo. Biochem Pharmacol 31:3839–3845, 1982.PubMedCrossRefGoogle Scholar
- 16.Spindler CD and Saunders PP: Characterization of tiazofurin phosphorylating activities in CHO cells. Proc Amer Assoc Cancer Res 26:248, 1985.Google Scholar
- 17.Fridland A and Connelly M: Adenosine kinase deficiency in cultured human lymphoblasts resistant to tiazofurin. Proc Amer Assoc Cancer Res 26:19, 1985.Google Scholar
- 25.Cooney DA, Jayaram HN, Ahluwalia GS, Dion RL, Zwelling LA, Kerrigan D, and Johns DG: Pharmacologic and physiologic consequences of resistance to tiazofurin. Proc 13th Intern Congress Chemotheraphy 17; 261/46–261/52, 1983.Google Scholar
- 26.Jayaram HN: Biochemical mechanisms of resistance to tiazofurin. Adv Enzyme Reg (in press), 1985.Google Scholar
- 27.Jayaram HN, Pillwein K, Lui MS, Faderan MA, and Weber G: Mechanism of resistance to tiazofurin in hepatoma 3924A. Biochem Pharmacol (in press), 1985.Google Scholar
- 28.Jayaram HN, Pillwein K, Nichols CR, Hoffman R, and Weber G: Sensitivity to tiazofurin of human normal, and leukemic leukocytes in vitro. J Clin Invest (in press), 1986.Google Scholar
- 32.Ahluwalia GS, Gebeyehu G, Jayaram HN, Cooney DA, Marquez VE, and Johns DG: Degradation of NAD/TAD analogs by a unique phosphodiesterase from Colon-38 tumor. Proc Amer Assoc Cancer Res 25:343, 1984.Google Scholar
- 33.Gebeyehu G, Marquez VE, VanCott A, Cooney DA, Kelley JA, Jayaram HN, Ahluwalia GS, Dion RL, Wilson YA, and Johns DG: Ribavirin, tiazofurin, and selenazofurin: Mononucleotides and nicotinamide adenine dinucleotide analogues; synthesis, structure and interactions with IMP dehydrogenase. J Med Chem 28:99–105, 1985.PubMedCrossRefGoogle Scholar
- 39.Sokoloski J A and Sartorelli AC: Induction of differentiation of HL-60 promyelocytic leukemia cells by inhibitors of IMP dehydrogenase. Proc Amer Asoc Cancer Res 25:42, 1984.Google Scholar