Related Experiment Videos
[Acquisition of resistance to anticancer agents by overproduction of target enzymes]
1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research.
Abstract:
Antimetabolic anticancer agents possess their own target enzymes: that of methotrexate is dihydrofolate reductase; 5-fluorouracil and ZD1604, thymidylate synthase; hydroxyurea, ribonucleotide reductase; 2'-deoxycoformycin, adenosine deaminase; N-(phosphonacetyl)-L-aspartate, aspartate transcarbamylase. Overproduction of each target enzyme has been observed with various animal and human cell lines which acquired resistance to all these agents. These facts suggest that this is a common mechanism for resistance to these agents. Most of these resistant cells showed amplification of the corresponding genes in double minute chromosome or homogeneously stained region of the chromosome. The relation between the degree of resistance and those of enzyme overproduction, the expression and amplification of the gene coding for each enzyme protein in various resistant cell lines are demonstrated and discussed.
Insights
Anticancer drug resistance in cancer cells is often caused by overproducing target enzymes like dihydrofolate reductase. Gene amplification in chromosomes explains this common resistance mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Context:
- Antimetabolic anticancer agents target specific enzymes crucial for cancer cell proliferation.
- Acquired resistance to these drugs is a significant clinical challenge.
- Understanding resistance mechanisms is vital for developing effective cancer therapies.
Purpose:
- To investigate the common mechanisms of acquired resistance to antimetabolic anticancer agents.
- To explore the role of target enzyme overproduction and gene amplification in drug resistance.
- To analyze the relationship between drug resistance levels, enzyme activity, and gene expression.
Summary:
- Antimetabolic anticancer drugs, including methotrexate and 5-fluorouracil, target specific enzymes such as dihydrofolate reductase and thymidylate synthase.
- Overproduction of these target enzymes is a frequently observed mechanism in drug-resistant cancer cell lines.
- Gene amplification, leading to increased enzyme levels, is often found in resistant cells, residing in double minute chromosomes or homogeneously stained regions.
Impact:
- This study highlights a common molecular mechanism underlying resistance to a class of anticancer drugs.
- Findings suggest that targeting enzyme overproduction or gene amplification could be potential therapeutic strategies.
- The research provides a foundation for further investigation into overcoming drug resistance in cancer treatment.