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Mechanisms underlying resistance to streptozotocin in Mer+ and Mer- human tumor lines
1Department of Medicine, University of Massachusetts Medical School, Worcester 01655.
Abstract:
Streptozotocin (STZ) is a monofunctional nitrosourea employed in the treatment of patients with islet cell tumors. To analyze the role of DNA repair mechanisms in causing resistance to STZ, we evaluated the cytotoxicity by this agent in three human tumor lines that differ with respect to their abilities to repair N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) damaged virus (the Mer phenotype). HT-29, A2182, and BE human tumor lines are high, intermediate and low, respectively, with regard to features that define the Mer phenotype. Our results demonstrated that the order of resistance to STZ is HT-29 greater than A2182 greater than BE. The degree of inhibition of DNA synthesis by STZ was in the following order: BE greater than A2182 greater than HT-29. O6-Alkyltransferase activity was increased markedly in HT-29 cells compared to A2182 cells which, in turn, had significantly increased levels compared to the BE line. Other potential factors such as 3-methyladenine DNA glycosylase activity, the induction by STZ of single-stranded DNA breaks, and the kinetics of repair of these breaks do not clearly underlie differences in cytotoxicity among the three tumor lines. However, increased topoisomerase II activity, as well as enhanced sensitivity to agents that interact with topoisomerase II, was present in A2182 cells compared to BE cells. These findings demonstrate that while O6-alkyltransferase contributes to resistance to STZ in some Mer+ tumor lines, other mechanisms may also contribute to resistance to this agent.
Insights
DNA repair mechanisms influence resistance to streptozotocin (STZ), a cancer drug. O6-alkyltransferase activity is a key factor, but other DNA repair pathways also contribute to STZ resistance in tumor cells.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Streptozotocin (STZ) is a nitrosourea used to treat islet cell tumors.
- DNA repair mechanisms are crucial in determining cancer treatment efficacy and drug resistance.
Purpose of the Study:
- To investigate the role of DNA repair mechanisms in conferring resistance to streptozotocin (STZ).
- To evaluate the cytotoxicity of STZ in human tumor cell lines with varying DNA repair capacities.
Main Methods:
- Assessed STZ cytotoxicity in HT-29, A2182, and BE human tumor lines with differing MNNG DNA repair phenotypes (Mer+).
- Measured O6-alkyltransferase activity, 3-methyladenine DNA glycosylase activity, and single-stranded DNA break repair kinetics.
- Evaluated topoisomerase II activity and sensitivity in relation to STZ resistance.
Main Results:
- Tumor cell resistance to STZ followed the order: HT-29 > A2182 > BE.
- DNA synthesis inhibition by STZ was greatest in BE cells and lowest in HT-29 cells.
- O6-alkyltransferase activity was significantly higher in HT-29 and A2182 cells compared to BE cells, correlating with resistance.
Conclusions:
- O6-alkyltransferase activity is a major contributor to STZ resistance in Mer+ tumor lines.
- Other DNA repair mechanisms, potentially involving topoisomerase II, may also play a role in STZ resistance.
- Understanding these mechanisms can inform strategies to overcome drug resistance in cancer therapy.