Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Dipyridamole potentiates the cytotoxicity of N10-propargyl-5,8-dideazafolic acid (CB3717), an antifolate inhibitor of thymidylate synthase, by inhibiting both thymidine (TdR) salvage and deoxyuridine (UdR) efflux. Dipyridamole binds to the serum component alpha 1acid glycoprotein (alpha 1AGP) and hence the effects of alpha 1AGP on dipyridamole-induced changes in nucleoside transport and CB3717 cytotoxicity have been investigated. Using A549 lung cancer cells in vitro, alpha 1AGP reduced the inhibition of nucleoside transport by dipyridamole in a concentration-dependent manner. Between 10 and 200 times the concentration of dipyridamole was needed to inhibit TdR uptake to the same degree in medium containing 1 mg/ml alpha 1AGP (a physiological concentration) when compared to the uptake in alpha 1AGP-free medium. Although dipyridamole inhibited UdR efflux more than TdR efflux, inhibition of UdR efflux was reduced less than the inhibition of TdR efflux in the presence of 1 mg/ml alpha 1AGP. Thus, clinically achievable levels of dipyridamole (2.5-7.5 microM), even in the presence of physiological alpha 1AGP concentrations, caused significant inhibition of nucleotide uptake and efflux. The cytotoxicity of CB3717 was increased 2-3-fold by 3 and 10 microM dipyridamole in alpha 1AGP-free medium, whereas dipyridamole did not significantly (P greater than or equal to 0.05) potentiate CB3717 cytotoxicity in the presence of 1 mg/ml alpha 1AGP. Measured free dipyridamole levels indicated that the impaired inhibition of nucleoside transport and the lack of potentiation of CB3717 cytotoxicity in the presence of alpha 1AGP was due solely to the binding of dipyridamole to alpha 1AGP. It is concluded that alpha 1AGP levels will be a major determinant of the ability of dipyridamole to modulate the activity of antimetabolites in vivo.

Type

Journal article

Journal

Biochem Pharmacol

Publication Date

01/10/1989

Volume

38

Pages

3281 - 3288

Keywords

Biological Transport, Cell Division, Dipyridamole, Drug Synergism, Folic Acid, Folic Acid Antagonists, Humans, Nucleosides, Orosomucoid, Quinazolines, Thymidine, Tumor Cells, Cultured