Biochemical Parameters of Resistance of an Adriamycin-Resistant Subline of P388 Leukemia to Emetine, an Inhibitor of Protein Synthesis

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Abstract
The effects of emetine on protein and DNA synthesis in vitro and in vivo were compared in P388 leukemia cells (P388/S) and in an adriamycin-resistant subline of P388 leukemia (P388/ADR), which was completely cross-resistant in vivo to emetine. in P388/ADR cells in vitro no apparent resistance to emetine was found; no difference in cytotoxicity was evident in P388/S or P388/ADR cells exposed to emetine in vitro for 1 or 6 hours. Protein and DNA synthesis was inhibited to a similar extent in P388/S and P3881 ADR cells at equivalent concentrations of the drug. However, inhibition of protein synthesis by emetine In P3881 ADR cells was more reversible than in P388/S cells when the cells were exposed to emetine and subsequently incubated in drug-free medium for 1 hour prior to addition of labeled l-leucine. Differences between P388/S and P388/ADR cells were evident in vivo. The duration of inhibition (>90%) of protein and DNA synthesis in P388/ADR cells was about 8 hours compared to 24 hours in P388/S cells following administration of a therapeutic dose of 25 mg emetine/kg to tumor-bearlng mice. The level of radioactivity in the P388/ADR cells 24 hours after in vivo administration of the emetine analog, (±)-[3′-14C]2,3-dehydroemetine, was only 26% of that in P388/S cells. This evidence suggests that the resistance of P388/ADR to emetine is due to decreased retention of the drug.