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Resistance to methotrexate and multidrug resistance in childhood malignancies
D Niethammer1, H Diddens, V Gekeler
1Department of Pediatrics, University of Tübingen, F.R.G.
Abstract:
Resistance to drugs, either primary or acquired, is a main problem in cancer chemotherapy. The paper summarizes our results in regard to resistance to methotrexate and multiple drug resistance in human cell lines of pediatric malignancies and in children with resistant cancer. In cell lines as well as in children we could demonstrate amplification of the gene coding for dihydrofolate reductase as a cause for resistance to MTX. Procedures to overcome drug resistance such as treatment with high dose MTX and leucovorin rescue are discussed. The increased expression of the mdrl gene coding for the P-glycoprotein is related to multidrug resistance. This could be shown in cell lines and in children. The expression decreased when the drug, used for induction of resistance, was omitted for a few weeks from the cell culture medium. Readdition of the drug caused a rapid increase of expression. For the first time data in children are presented which demonstrate the amplification of the gene coding for dihydrofolate reductase or increased expression of the mdrl gene as cause of drug resistance. The clinical implications of these findings are discussed.
Insights
Drug resistance in pediatric cancers is a major challenge. This study identifies gene amplification for dihydrofolate reductase and MDR1 gene expression as key causes of resistance in children, offering insights for treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance, both primary and acquired, significantly impedes effective cancer chemotherapy.
- Understanding the molecular mechanisms of resistance is crucial for developing improved therapeutic strategies in pediatric malignancies.
Purpose of the Study:
- To investigate the molecular basis of methotrexate (MTX) resistance and multidrug resistance (MDR) in human pediatric cancer cell lines and in children with resistant cancers.
- To identify specific genetic alterations and gene expression patterns associated with drug resistance in pediatric malignancies.
Main Methods:
- Analysis of gene amplification for dihydrofolate reductase (DHFR) in cell lines and patient samples.
- Assessment of multidrug resistance 1 (mdr1) gene expression, coding for P-glycoprotein, in relation to MDR.
- Evaluation of the impact of drug withdrawal and reintroduction on mdr1 gene expression in cell cultures.
Main Results:
- Gene amplification of DHFR was confirmed as a cause of MTX resistance in both pediatric cancer cell lines and children.
- Increased expression of the mdr1 gene, encoding P-glycoprotein, was associated with MDR in cell lines and pediatric patients.
- Reversible modulation of mdr1 gene expression was observed in response to drug exposure in cell culture, highlighting dynamic resistance mechanisms.
Conclusions:
- This study provides the first data in children demonstrating DHFR gene amplification and mdr1 gene overexpression as causative factors for drug resistance in cancer.
- The findings underscore the clinical relevance of these molecular mechanisms and suggest potential therapeutic avenues, such as high-dose MTX with leucovorin rescue, to overcome resistance.