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Modulation of antitumor alkylating agents by novobiocin, topotecan, and lonidamine
G N Schwartz1, B A Teicher, J P Eder
1Dana-Farber Cancer Institute, Boston, MA 02115.
Abstract:
Topoisomerase I and topoisomerase II allow a metabolically active cell to mobilize its supercoiled chromosomal DNA and undergo replication, transcription, recombination, and repair. Several topoisomerase inhibitors have recently been shown to be active in preclinical systems. Topotecan (SK&F 104,864), a water-soluble camptothecin analog, is an inhibitor of topoisomerase I. Novobiocin is an inhibitor of topoisomerase II. Lonidamine depletes cellular adenosine 5'-triphosphate (ATP) and may impede energy-dependent DNA repair, MCF-7 human breast-cancer cells were treated in vitro with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP and melphalan. The three enzyme inhibitors alone and in combination did not increase tumor cell sensitivity to CDDP. However, the combinations of topotecan/novobiocin and lonidamine/novobiocin did enhance the cytotoxicity of melphalan. Mice bearing the FSaII fibrosarcoma were treated in vivo with topotecan, novobiocin, and lonidamine alone, in paired combinations, and in combination with CDDP, melphalan, BCNU, and cyclophosphamide. The combination of topotecan/novobiocin had the greatest impact on tumor cell sensitivity to each cytotoxic agent tested in both tumor cell-survival and tumor growth-delay assays. This sensitization was greatest at the highest concentrations of the cytotoxic agent tested. Combinations of topoisomerase I and topoisomerase II inhibitors may be useful as modulators of antitumor alkylating agents.
Insights
Combining topoisomerase I and II inhibitors enhances chemotherapy effectiveness. Specifically, topotecan and novobiocin combinations significantly improved sensitivity to alkylating agents in preclinical cancer models.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Topoisomerases I and II are crucial enzymes for DNA metabolism, enabling replication, transcription, and repair.
- Topoisomerase inhibitors are emerging as potential therapeutic agents in preclinical cancer research.
- Topotecan inhibits topoisomerase I, novobiocin inhibits topoisomerase II, and lonidamine affects cellular ATP levels.
Purpose of the Study:
- To evaluate the in vitro and in vivo effects of topoisomerase inhibitors alone and in combination with cytotoxic agents on cancer cells.
- To determine if topoisomerase inhibitors can sensitize tumor cells to chemotherapy, including CDDP and melphalan.
- To investigate the potential of combining topoisomerase I and II inhibitors as modulators of antitumor alkylating agents.
Main Methods:
- MCF-7 human breast-cancer cells were treated in vitro with topotecan, novobiocin, and lonidamine, alone and in combinations, with and without CDDP and melphalan.
- FSaII fibrosarcoma-bearing mice were treated in vivo with topotecan, novobiocin, and lonidamine, alone and in combinations, with CDDP, melphalan, BCNU, and cyclophosphamide.
- Tumor cell sensitivity was assessed using cell-survival and tumor growth-delay assays.
Main Results:
- Topoisomerase inhibitors alone or with CDDP did not enhance tumor cell sensitivity.
- Combinations of topotecan/novobiocin and lonidamine/novobiocin increased melphalan cytotoxicity in vitro.
- The topotecan/novobiocin combination demonstrated the most significant sensitization of tumor cells to various cytotoxic agents in vivo.
Conclusions:
- Combinations of topoisomerase I and II inhibitors show promise in enhancing the efficacy of antitumor alkylating agents.
- The synergistic effect is most pronounced at higher concentrations of cytotoxic agents.
- Further research into combined topoisomerase inhibition could lead to improved cancer treatment strategies.