DNA topoisomerase II as a potential factor in drug resistance of human malignancies
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Abstract:
The stabilization of the cleavable complex between DNA topoisomerase II and DNA by adriamycin (ADR), as well as by other topoisomerase II-targeted drugs, is an essential step in a process associated with drug cytotoxicity. Unlike many other cell types, ADR does not produce DNA cleavage in the lymphocytes of chronic lymphocytic leukemia (CLL). The CLL lymphocytes have been identified as quiescent cells with an extremely low level of topoisomerase II. The low level of this enzyme could constitute a basis for a new mechanism of drug resistance operating not only in CLL, but perhaps in any slow growing cancer with a large population of quiescent cells. Other factors contributing to drug resistance could include changes in enzyme regulation or processing of the cleavable complex, or the presence of a "mutant" enzyme which renders cancer cells unresponsive to topoisomerase II-targeted drugs. Suggested strategies in drug development, aimed at the topoisomerase II-related drug resistance, could include 1) the selection of topoisomerase I as an alternative target for cancer chemotherapy, 2) the development of ADR analogs which, unlike ADR, stabilize the topoisomerase II-DNA complex with high efficiency, and 3) the search for agents enhancing the SOS-like repair response, presumably triggered by DNA topoisomerase-targeted drugs.
Insights
Adriamycin (ADR) drug resistance in chronic lymphocytic leukemia (CLL) may stem from low topoisomerase II enzyme levels in quiescent cells. This finding suggests new drug resistance mechanisms and therapeutic strategies for slow-growing cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Adriamycin (ADR) and similar drugs target DNA topoisomerase II, stabilizing the enzyme-DNA complex to induce cytotoxicity.
- Chronic lymphocytic leukemia (CLL) lymphocytes exhibit resistance to ADR-induced DNA cleavage, unlike most other cell types.
Purpose of the Study:
- To investigate the mechanism of ADR resistance in CLL lymphocytes.
- To explore the role of DNA topoisomerase II levels in drug resistance.
- To identify potential new strategies for overcoming topoisomerase II-targeted drug resistance in cancer.
Main Methods:
- Analysis of DNA topoisomerase II levels in quiescent CLL lymphocytes.
- Comparison of ADR's effect on DNA cleavage in CLL cells versus other cell types.
- Review of potential mechanisms contributing to topoisomerase II-targeted drug resistance.
Main Results:
- CLL lymphocytes possess an extremely low level of DNA topoisomerase II.
- ADR does not induce DNA cleavage in CLL lymphocytes, indicating a resistance mechanism.
- Low enzyme levels in quiescent cells may represent a novel drug resistance mechanism applicable to slow-growing cancers.
Conclusions:
- The low expression of DNA topoisomerase II in quiescent CLL cells is a potential basis for drug resistance.
- Drug resistance may also involve altered enzyme regulation, complex processing, or mutations.
- Future strategies could involve targeting topoisomerase I, developing potent ADR analogs, or enhancing DNA repair responses.