The effects of purine nucleoside analogs on the response of the RIF-1 tumor to melphalan in vivo.

The effect of several purine nucleoside analogs on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumor in vivo was investigated. All the analogs tested--3'-deoxyguanosine (3'-dG), 3'-deoxyadenosine (3'-dA), and N6-butyryl-3'-deoxyadenosine (N6-BC)--at a dose of 100 mg/kg, enhanced the tumor cell killing by L-PAM as measured by an in vivo/in vitro procedure. This enhancement was maximal when the drugs were given simultaneously. The mean enhancement ratios (ER's) determined from the L-PAM dose response curves were 1.4 for 3'-dG, 1.3 for 3'-dA, and 1.4 for N6-BC. A similar modification of the L-PAM-induced depression of white blood cell counts was not obtained. A large single dose of L-PAM (8 mg/kg) produced a transient drop in mouse body temperature. The analog 3'-dG (100 mg/kg) increased and prolonged this hypothermic effect. In addition 3'-dG also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 28 minutes to 35 minutes. The enhancement of the efficacy of L-PAM by these analogs probably results from this pharmacokinetic effect.