Synergistic action of tiazofurin and difluorodeoxycytidine on differentiation and cytotoxicity

Ban, Jasna; Weber, George

doi:10.1016/0006-291x(92)90625-u

Cited by 6 publications

(6 citation statements)

References 12 publications

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“….I=1-f| (l-in) (1) n=1 where I is the predicted fractional inhibition produced by the combination and i is the fractional inhibition produced by n drugs used individually. Equation 1 is the general form of equation 2, which is the dissimilar-site additivity equation described previously (21,22):…”

Section: Chemicals Apts Was Prepared By Derse and Schroedermentioning

confidence: 99%

“…Equation 1 is the general form of equation 2, which is the dissimilar-site additivity equation described previously (21,22):…”

Section: Chemicals Apts Was Prepared By Derse and Schroedermentioning

confidence: 99%

“…Additionally, the emergence of drug-resistant mutants is a significant problem in single-drug therapy (3). Treatment with combinations of antiviral agents is generally thought to minimize drug resistance (1,6,14) but may or may not offer increased selectivity and efficacy. Traditionally, drug combinations have been chosen on the basis of the potency and/or efficacy of the individual agents.…”

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confidence: 99%

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Strategic design and three-dimensional analysis of antiviral drug combinations

Prichard

Shipman

1993

Antimicrob Agents Chemother

106

117

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The development of new drugs effective against human viral diseases has proven to be both difficult and time-consuming. Indeed, there are but 10 drugs licensed for such applications in the United States today. An attractive solution to this problem may be to optimize the efficacy and selectivity of existing antiviral drugs by combining them with agents that strategically block carefully selected metabolic pathways. This approach was used in the rational design of a three-drug combination to increase the apparent potency of acyclovir against herpes simplex virus. Recent advances in analytical techniques have made the evaluation of this complex drug strategy both possible and practical. A modified version of a previously described analytical method was used to identify optimal drug concentrations and to quantitate statistically significant synergy. Concentrations of 0.25 ,M 5-fluorodeoxyuridine, 3.6 ,uM 2-acetlpyridine thiosemicarbazone, and 0.3 ,uM acyclovir were determined to be optimal in terms of antiviral activity. The volume of synergy produced was nearly 2,000 ,uM3% at a 95% level of confidence (corresponding to a 186-fold decrease in the apparent 50%o inhibitory concentration of acyclovir with the addition of 0.25 ,uM 5-fluorodeoxyuridine and 3.6 ,uM 2-acetylpyridine thiosemicarbazone). We anticipate that this strategic approach and the supporting three-dimensional analytical method will prove valuable in designing and understanding multidrug therapies.Antiviral drugs derive their specificity through the preferential inhibition of virus-encoded enzymes present in infected cells (13). The usefulness of these agents is limited by the degree to which they concomitantly affect uninfected cells, producing untoward toxicity. Additionally, the emergence of drug-resistant mutants is a significant problem in single-drug therapy (3). Treatment with combinations of antiviral agents is generally thought to minimize drug resistance (1, 6, 14) but may or may not offer increased selectivity and efficacy. Traditionally, drug combinations have been chosen on the basis of the potency and/or efficacy of the individual agents. The component drugs often have been active against the same target, and detailed evaluations of drug interactions often have been lacking. Combiwitions of drugs that inhibit different targets, however, often offer surprising potency, even though one or more of the constituent c6mpounds may be weakly active. We now describe the rational design of an antiviral combination of three drugs that strategically inhibits the replication of herpes simplex virus (HSV) by blocking carefully chosen metabolic pathways. Evaluation of this strategy and the determination of optimal drug concentrations were made possible by recent advances in existing three-dimensional analytical procedures (21, 22).The rational design of a combination of drugs relies on a thorough understanding of drug metabolism in both virusinfected and uninfected cells. The antiherpesvirus drug acyclovir (ACV; Zovirax) is a potent inhibitor of HSV re...

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Section: Chemicals Apts Was Prepared By Derse and Schroedermentioning

confidence: 99%

“…Equation 1 is the general form of equation 2, which is the dissimilar-site additivity equation described previously (21,22):…”

Section: Chemicals Apts Was Prepared By Derse and Schroedermentioning

confidence: 99%

mentioning

confidence: 99%

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Strategic design and three-dimensional analysis of antiviral drug combinations

Prichard

Shipman

1993

Antimicrob Agents Chemother

106

117

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“…Figure 3 shows the structure of gemcitabine (2',2'-difluorodeoxycitidine, DFDC) and its active metabolite and the enzymic and metabolic bases of the synergistic action of tiazofurin and gemcitabine. The ability of gemcitabine to induce differentiation was first shown by Ban and Weber [16]. Since gemcitabine decreased dCTP levels and tiazofurin decreased dGTP concentrations (Fig.…”

Section: Tiazofurin and Ribavirin: Synergistic In Inducing Differentimentioning

confidence: 99%

“…The missing Jink has recently been tested by direct determination of the Ras-GTP complex in tiazofurin-treated cells [17]. Exposure of K562 cells to tiazofurin resulted in a time- Enzymatic basis of the synergistic action of tiazofurin and gemcitabine [16] ~) ))) )))))) ))))) ))))) )))))))) ))))) )) )))))))))))))))))))))))))))))))))))) )))))))))))))))))))))))))))))))))))))) and concentration-dependent decrease in Ras-GTP ~|e~t:~ !g ~ if! ~ ~fu~in~~as ~ [17].…”

Section: Molecular Mechanisms Of Induced Differentiation By Tiazofuriunclassified

Role of differentiation induction in action of purine antimetabolites

1994

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In cancer cells, particularly in leukaemic cells, guanylate biosynthesis is up-regulated as shown by the increased activities of IMP dehydrogenase, the rate-limiting enzyme of de novo GTP biosynthesis, and of the salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity. A triad of responses was observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras and c-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and gemcitabine [corrected]. Induced differentiation plays an important role in the overall impact of antipurine agents.

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