Effects of hydroxyurea and thymidine derivatives on the uptake and metabolism of deoxycytidine and arabinofuranosylcytosine in log phase and contact-inhibited human diploid fibroblasts.

Hydroxyurea and pyrimidine analogs have been shown to enhance the chemotherapeutic efficacy and the DNA excision repair-inhibitory capacity of arabinofuranosylcytosine (ara-C). Since various cell types are expected to respond differently to these combination treatments and since little is known about the nature of their antiproliferative effects, we have investigated the metabolism and uptake into acid-soluble pools of deoxycytidine (dCyd) and ara-C in cycling and non-cycling human diploid fibroblasts. A substantial fraction of dCyd is converted through deamination to deoxyuridine and thymidine nucleotides, and this occurs to a greater degree in log phase cultures. ara-C is more resistant to deamination and is metabolized primarily to ara-CTP. Hydroxyurea decreases the proportion of dCyd and ara-C which is deaminated under both growth conditions, leading to higher levels of ara-CTP and dCTP. Trifluorothymidine causes an accumulation of dUMP and decreases the formation of dCTP in log phase and confluent cells. Thymidine inhibits deamination in log phase cells but stimulates this pathway in noncycling cells. Dideoxythymidine did not appreciably alter the spectrum of metabolites of dCyd formed in log or confluent phase cells but was shown to inhibit the transport of dCyd and thymidine across the membrane. These studies provide information regarding the nature of the enhancement of the antiproliferative activity of ara-C by commonly used drugs and indicate that the cycling state of the target cell plays a major role in determining the metabolism of the nucleoside and the efficacy of chemotherapeutic treatments.