Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells

Hiremagalur N. Jayaram, Kimie Murayama, Konrad Pillwein, Weining Zhen, George Weber

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Tiazofurin is an oncolytic nucleoside analog that has shown therapeutic activity in end-stage acute non-lymphocytic leukemia and in chronic granulocytic leukemia in blast crisis. Tiazofurin is anabolized to the active metabolite, TAD, which inhibits IMP dehydrogenase activity, leading to a reduction in guanylate pools and to the cessation of neoplastic cell proliferation. The drug exhibits potent cytostatic and cytotoxic activity against hepatoma 3924A cells in culture. In growth-inhibition and clonogenic assays, the 50% inhibitory concentration of tiazofurin was 3.8 and 4.2 μm, respectively. Dipyridamole, an inhibitor of nucleoside transport, curtails the salvage of nucleosides and bases for nucleotide biosynthesis. Dipyridamole exhibited cytotoxicity against hepatoma 3924A cells, with an LC50 of 24 μm and an IC50 of 29 μm being recorded. A combination of tiazofurin and dipyridamole provided synergistic cytotoxicity in hepatoma 3924A cells in culture. This synergistic activity was dependent on the order of addition of the drugs. Simultaneous addition of the two drugs produced antagonism, whereas preincubation of cells with tiazofurin or dipyridamole followed by addition of the second drug resulted in synergy. TAD concentrations were significantly higher (129% and 135%) in cells that had been pretreated with tiazofurin or dipyridamole before the addition of the second agent as compared with cells that had been treated simultaneously (113%). These studies indicate the importance of the order of the addition of drugs to obtain a synergistic response in combination chemotherapy and suggest the need for a careful selection of drug modulation in clinical trials of tiazofurin and dipyridamole.

Original languageEnglish (US)
Pages (from-to)93-96
Number of pages4
JournalCancer Chemotherapy and Pharmacology
Volume31
Issue number2
DOIs
StatePublished - Mar 1 1992

Fingerprint

tiazofurin
Dipyridamole
Hepatocellular Carcinoma
Appointments and Schedules
Nucleosides
Pharmaceutical Preparations
Cytotoxicity
Inhibitory Concentration 50
Drug Antagonism
Cell Culture Techniques
IMP Dehydrogenase
Blast Crisis
Salvaging
Chemotherapy
Biosynthesis
Cell proliferation
Cytostatic Agents
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Metabolites
Combination Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells. / Jayaram, Hiremagalur N.; Murayama, Kimie; Pillwein, Konrad; Zhen, Weining; Weber, George.

In: Cancer Chemotherapy and Pharmacology, Vol. 31, No. 2, 01.03.1992, p. 93-96.

Research output: Contribution to journalArticle

Jayaram, Hiremagalur N. ; Murayama, Kimie ; Pillwein, Konrad ; Zhen, Weining ; Weber, George. / Schedule-dependent synergistic action of tiazofurin and dipyridamole on hepatoma 3924A cells. In: Cancer Chemotherapy and Pharmacology. 1992 ; Vol. 31, No. 2. pp. 93-96.
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