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Resistance to anticancer drugs in NIH3T3 cells transfected with c-myc and/or c-H-ras genes
S Niimi1, K Nakagawa, J Yokota
1Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
NIH3T3 cells transfected with c-H-ras and/or c-myc genes were examined for differences in drug sensitivity. The five transfectants used were N8, NIH3T3-nm-1, pT22-3-nm-2, pP1-4 and pT22-3. They were transfected with pKOneo alone, pKOneo and c-myc, pKOneo and c-myc plus activated c-H-ras, normal c-H-ras and activated c-H-ras genes, respectively. The IC50s of cisplatin, 4-hydroperoxycyclophosphamide, adriamycin, melphalan, and CPT-11 were significantly higher for NIH3T3-nm-1 abd pT22-3-nm-2 than for the parental NIH3T3 and N8 cells. Transfection with normal and activated C-H-ras oncogenes only led to increases in the IC50s of alkylating agents. There was no significant difference between the IC50s of N8 and those of NIH3T3 parental cells to any of these anticancer agents. These results strongly suggest that the expression of the c-myc gene plays a role in the acquisition of drug resistance. The c-myc gene may therefore provide us with an important clue in determining the mechanism of drug resistance.
Insights
The c-myc gene significantly increases cancer drug resistance in NIH3T3 cells. This finding offers crucial insights into the mechanisms underlying multidrug resistance, potentially aiding in developing more effective cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Oncogenes like c-H-ras and c-myc are frequently implicated in cancer development.
- Understanding the role of specific genes in drug resistance is crucial for effective cancer treatment.
- NIH3T3 cells serve as a model system for investigating genetic modifications and their cellular effects.
Purpose of the Study:
- To investigate the impact of c-H-ras and c-myc gene transfection on the drug sensitivity of NIH3T3 cells.
- To determine if c-myc gene expression contributes to acquired resistance against various anticancer agents.
- To explore the potential role of c-myc in the mechanisms of multidrug resistance.
Main Methods:
- NIH3T3 cells were transfected with various combinations of pKOneo, c-myc, and c-H-ras genes.
- Five distinct transfectant cell lines (N8, NIH3T3-nm-1, pT22-3-nm-2, pP1-4, pT22-3) were generated.
- The half-maximal inhibitory concentrations (IC50s) of cisplatin, 4-hydroperoxycyclophosphamide, adriamycin, melphalan, and CPT-11 were measured for each cell line.
Main Results:
- NIH3T3 cells expressing c-myc (NIH3T3-nm-1 and pT22-3-nm-2) exhibited significantly higher IC50 values for multiple anticancer drugs compared to parental cells.
- Transfection with c-H-ras oncogenes alone increased resistance specifically to alkylating agents.
- No significant difference in drug sensitivity was observed between parental NIH3T3 cells and N8 cells (transfected with pKOneo alone).
Conclusions:
- The expression of the c-myc gene plays a significant role in the acquisition of resistance to various anticancer drugs.
- c-myc mediated drug resistance may involve mechanisms distinct from those induced by c-H-ras.
- The c-myc gene is a potential key factor in understanding and overcoming multidrug resistance in cancer.