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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
In vitro assessment of nucleoside analogs in multiple myeloma
Nancy L Krett1, Mary Ayres, Chadi Nabhan
1Division of Hematology and Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA. n-krett@northwestern.edu
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 microM gemcitabine triphosphate but accumulated <20 microM 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 nM 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.
Insights
Gemcitabine shows potent activity against multiple myeloma (MM) cell lines, including drug-resistant types. Its effectiveness stems from superior intracellular metabolism and induction of apoptosis, making it a promising nucleoside analog for MM treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells.
- Developing novel therapeutic agents, including nucleoside analogs, is crucial for overcoming drug resistance in MM.
- Identifying potent nucleoside analogs with favorable metabolic profiles is a key research area in MM treatment.
Purpose of the Study:
- To evaluate the efficacy of various nucleoside analogs, including fludarabine, clofarabine, and gemcitabine, against multiple myeloma (MM) cell lines.
- To identify nucleoside analogs that demonstrate potent activity, particularly in MM cell lines resistant to conventional chemotherapy.
Main Methods:
- Utilized biologic and biochemical assays to assess the activity of selected nucleoside analogs in MM cell lines.
- Quantified intracellular triphosphate metabolite accumulation and measured DNA synthesis inhibition.
- Assessed gemcitabine's dose- and time-dependent effects on apoptosis induction via subG1 DNA content analysis.
Main Results:
- Gemcitabine, fludarabine, and clofarabine exhibited the most potent activity among the tested nucleoside analogs.
- MM cell lines resistant to standard chemotherapeutics showed increased sensitivity to gemcitabine, with IC50 values in the nanomolar range.
- Gemcitabine demonstrated superior intracellular accumulation as gemcitabine triphosphate compared to other analogs, correlating with enhanced cytotoxicity and DNA synthesis inhibition, ultimately inducing apoptosis.
Conclusions:
- Gemcitabine is a highly potent nucleoside analog against multiple myeloma cell lines, including those with resistance to other agents.
- The enhanced efficacy of gemcitabine is attributed to its favorable intracellular metabolism, leading to greater triphosphate accumulation and potent anti-myeloma activity.
- These findings support gemcitabine's potential as a valuable therapeutic option for multiple myeloma treatment.
