PLDR inhibitors: their biological and clinical implications

Effects of various nucleoside analogues on X-ray-induced-PLD recovery (PLDR) were examined in plateau phase Chinese hamster HA-1 cells. Among the chemicals tested, 3'-dA (3'-deoxyadenosine) and ara-A (9-beta-D-arabinofuranosyladenine) were most potent inhibitors of PLDR at their slightly toxic doses. N6-butyryl-3'-dA and 3'-dG (3'-deoxyguanosine) were the most effective in suppressing PLDR at non-toxic doses. A specific inhibitor of DNA polymerase beta, 2', 3'-ddT (dideoxythymidine) was intermediately effective. However, possibly due to the lower intracellular incorporation or phosphorylation, 3'-deoxy-pyrimidine analogues and formycin B were less or non-effective. The enhancement of antitumor effect of cyclophosphamide by ara-A and 3'-dG was observed in SCC VII tumors in vivo. The involvement of DSB (or chromosome aberration) and SSB as well as base damage or crosslinks in PLD is suggested, since recently they have been shown not to be rejoined when treated with various agents such as hyperthermia and ara-A.