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[Circumventing drug resistance in human tumors by antisense ribozyme]
1Dept. of Clinical Laboratory and Medicine, Tohoku University School of Medicine.
Abstract:
The results presented here demonstrate that expression of a fos ribozyme limits Fos protein synthesis and enhances sensitivity of A2780DDP cells to antineoplastic agents, including cisplatin. Moreover, the reversal of this resistance is associated with down-regulation of dTMP synthase, DNA polymerase beta, topoisomerase I and hMT II-A, which are genes previously linked to DNA synthesis and repair. Thus, these studies further implicate the role of the c-fos gene in DNA synthesis through modulation of expression of dTMP synthase, DNA polymerase beta and topoisomerase I. Finally, the use of ribozymes to circumvent drug resistance suggests their potential utility as agents to inhibit tumor cell growth.
Insights
A fos ribozyme limits Fos protein synthesis, enhancing cancer cell sensitivity to chemotherapy. This approach shows potential for inhibiting tumor growth by targeting DNA synthesis and repair genes.
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Therapy
Context:
- Cisplatin resistance is a major challenge in treating ovarian cancer.
- The c-fos gene plays a role in cellular processes.
- Ribozymes offer a novel approach to gene regulation.
Purpose:
- To investigate the effect of a fos ribozyme on Fos protein synthesis.
- To determine if ribozyme expression can overcome cisplatin resistance in A2780DDP cells.
- To explore the molecular mechanisms underlying ribozyme-mediated sensitization.
Summary:
- Expression of a fos ribozyme effectively reduced Fos protein levels.
- This reduction enhanced the sensitivity of A2780DDP cells to cisplatin and other antineoplastic agents.
- Reversal of drug resistance correlated with decreased expression of genes involved in DNA synthesis and repair, including dTMP synthase, DNA polymerase beta, topoisomerase I, and hMT II-A.
Impact:
- These findings highlight the role of the c-fos gene in DNA synthesis and repair.
- Ribozymes demonstrate potential as therapeutic agents to overcome drug resistance and inhibit tumor cell proliferation.
- This study provides a foundation for developing novel gene-based strategies in cancer therapy.