The enhancement of the frequency of resistance to N-phosphonoacetyl-L-aspartate and methotrexate by 1-beta-D-arabinofuranosylcytosine: the effect of dipyridamole.

In cultured cells, dipyridamole, in a dose-dependent manner, prevented the enhancement by 1-beta-D-arabinofuranosylcytosine (AraC) of either N-phosphonoacetyl-L-aspartate (PALA)- or methotrexate- resistance frequency. Maximal blockade of enhancement of PALA-resistance frequency occurred if the dipyridamole was added with or within about 20 hr of PALA addition. Thereafter, the effect of dipyridamole decreased. Nitrobenzylthioinosine similarly reduced AraC enhancement of PALA- and methotrexate-resistance frequency. Both dipyridamole and nitrobenzylthioinosine inhibited uridine and thymidine uptake into cells to a similar extent in cells pretreated or not with AraC. Thus, although inhibition of nucleoside uptake would seem a reasonable explanation for the effect on PALA-resistance frequency by dipyridamole, there is no obvious explanation at present of how dipyridamole selectively affects resistance frequency in AraC-pretreated cells.