Enhancement of 5-fluorouracil's anticancer activity by dipyridamole

Grem, Jean L.; Fischer, Paul

doi:10.1016/0163-7258(89)90084-3

Cited by 50 publications

(21 citation statements)

References 63 publications

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“…Attempts have been made to exploit nucleoside salvage pathways in order to improve chemotherapy results. For example, potentiating the uptake and phosphorylation of ara-C by depleting the endogenous dCTP pool with hydroxyurea (Walsh et al, 1980;Rauscher and Cadman, 1983) or inhibiting these processes with agents such as dipyridamole to increase the effectiveness of MTX or 5-FU (Cabral et al, 1984;Wadler et al, 1987;Grem and Fischer, 1989).…”

Section: -(Saenta-x8)-fluorescein Binding Assaymentioning

confidence: 99%

“…Thus, preformed nucleosides did not alter the expression of es, consistent with the lack of modulation of es expression observed with TdR in our studies. Hydroxyurea concentration (gM) (Cabral et al, 1984;Wadler et al, 1987) and 5-FU (Grem and Fischer, 1989), that inhibit the de novo synthesis of DNA precursors. Attempts have been made to exploit nucleoside salvage pathways in order to improve chemotherapy results.…”

Section: -(Saenta-x8)-fluorescein Binding Assaymentioning

confidence: 99%

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Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

Pressacco

Wiley²,

Jamieson³

et al. 1995

Br J Cancer

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In contrast, cytosine arabinoside (ara-C) and aphidicolin, which directly inhibit DNA synthesis, produced no significant increase in es expression. Thymidine (TdR), which is an allosteric inhibitor of ribonucleotide reductase that depletes dATP, dCTP and dGTP pools while repleting the dTTP pool, had no significant effect on es expression. These data suggest that surface expression of the es nucleoside transporter is regulated by a mechanism which is sensitive to the supply of deoxynucleotides. Because 5-FU (which specifically depletes dTTP pools) causes a large increase in expression whereas TdR (which depletes all precursors except dTTP) does not, this mechanism might be particularly sensitive to dTTP pools.

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Section: -(Saenta-x8)-fluorescein Binding Assaymentioning

confidence: 99%

Section: -(Saenta-x8)-fluorescein Binding Assaymentioning

confidence: 99%

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

Pressacco

Wiley²,

Jamieson³

et al. 1995

Br J Cancer

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“…It has been shown, however, that dipyridamole's inhibitory effect on nucleoside transport may depend on the free drug concentration rather than the total drug concentration in vitro (7). The free drug level may therefore be critical to the antiviral effect.…”

Section: Discussionmentioning

confidence: 99%

Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects

Hendrix

Flexner

Szebeni

et al. 1994

Antimicrob Agents Chemother

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Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug.Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5-to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions. Both objectives are essential for planning studies of the efficacy of the zidovudine-dipyridamole combination. Eleven asymptomatic HIV-infected subjects (median CD4+ cell count, 311 cells per mm3), 10 of whom had been on zidovudine at 500 mg/day for at least 6 months, were admitted to the study. Zidovudine pharmacokinetics were measured on day 1. Dipyridamole was then begun at 600 mg/day (subjects 1 to 3) or 450 mg/day (subjects 4 to 11), and zidovudine and dipyridamole pharmacokinetics were measured on day 5. All subjects given 600 mg of dipyridamole per day developed headache or nausea, or both. Six of eight subjects given dipyridamole at 450 mg/day developed headache or mild nausea that resolved after a median of 2 days. The area under the zidovudine concentration-time curve was not significantly different on day 1 in comparison with that on day 5 (P = 0.11). Symptoms were significantly correlated with the maximum zidovudine concentrations, which were achieved when dipyridamole was dosed concomitantly (p = 0.03). Total (free and protein-bound) dipyridamole trough concentrations were near those demonstrating synergy with zidovudine against HIV in vitro. Dipyridamole was highly protein bound, with a median free/total dipyridamole ratio of 0.7%; the percent free/total dipyridamole ratio was inversely correlated with alpha, acid glycoprotein concentrations (r2 = 0.66).Results of the study indicate that adjustment of the zidovudine dose was not required to achieve equivalent zidovudine concentrations when zidovudine was administered in combination with dipyridamole at the doses studied. In the short study described here, the zidovudine-dipyridamole combination was well tolerated in asymptomatic HIV-infected subjects after the occurrence of mild transient symptoms.

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“…The Hep-2 cell line is derived from transformed laryngeal carcinoma cells (Birb and Forrester, 1981) and is frequently used in models for the study of carcinogenesis and mutagenesis (Grem and Fischer, 1989;Valdovinos and Gomez, 2003;Sinico et al, 2002). This line has a high proliferation rate, a 23-hours' cell cycle (Den Beste et al, 1966), and during mitosis a great number of cells loose cellular adhesion and remain suspended in the culture medium (Freshney, 1988).…”

Section: Introductionmentioning

confidence: 99%

Drifter technique: a new method to obtain metaphases in Hep-2 cell line cultures

Lima

Rissino

Guimarães

et al. 2005

Braz. arch. biol. technol.

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Enhancement of 5-fluorouracil's anticancer activity by dipyridamole

Cited by 50 publications

References 63 publications

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

Modulation of the equilibrative nucleoside transporter by inhibitors of DNA synthesis

Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects

Drifter technique: a new method to obtain metaphases in Hep-2 cell line cultures

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