In vitro assessment of nucleoside analogs in multiple myeloma

Purpose: To identify nucleoside analogs that may be effective for multiple myeloma (MM), we tested fludarabine, clofarabine, arabinosylguanine, cytarabine, troxacitabine, and gemcitabine in MM cell lines. Methods: We employed biologic and biochemical assays in MM cell lines to evaluate the clinical potential of these nucleoside analogs. Results: Among these purine and pyrimidine nucleoside analogs, fludarabine, clofarabine and gemcitabine were the most potent. MM cell lines, resistant to commonly used chemotherapeutic agents for this disease, were more sensitive to gemcitabine with an IC₅₀ in the nanomolar range. The greater cytotoxicity of gemcitabine in MM cells was consistent with greater accumulation of gemcitabine triphosphate, the major cytotoxic metabolite of this drug. MM.1S cells accumulated > 100 μM gemcitabine triphosphate but accumulated < 20 μM of the other analogs as the respective triphosphates. In addition incubation with gemcitabine resulted in inhibition of DNA synthesis. Incubation with 25, 50 or 100 n M gemcitabine resulted in a dose- and time-dependent increase in the cell population with a subG₁ DNA content indicative of apoptosis. Conclusions: These results suggest that gemcitabine is a potent nucleoside analog in MM cell lines including cell types resistant to other chemotherapeutic agents. The greater activity of gemcitabine compared to other analogs seems to be due to favorable metabolism of this agent.