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[Mechanism of action and resistance of antineoplastic agents]
Abstract:
The mechanisms of action of, and resistance to, important anticancer agents are briefly described. Their selective toxicity is considerably high, and is chiefly due to the distribution and metabolism in the body. The selective toxicity of some DNA-binding drugs may be attributed to the structural difference of DNA, nucleosome and/or chromatin between neoplastic and normal cells. Some studies of reducing side effects are summarized. In our laboratory, we are studying drug-resistance and metastasis of tumor cells. Since the mechanism of natural resistance of gastric cancer, pulmonary cancer, and other refractory cancers may be related to acquired resistance of leukemia, studies on new agents against drug-resistant tumor cells are important. In our laboratory, we have selected cell sublines of murine T-lymphoblastoma L5178Y for resistance to adriamycin (ADM), aclarubicin (ACR) or bleomycin (BLM), and have observed that the resistance is attributed to decreased influx and increased efflux of the antibiotic, resulting in lowered retention of the drug in the cells. Each resistant subline shows a characteristic cross-resistant pattern, suggesting that membrane alteration involved differs each other. We have also found that glycoprotein-synthesizing activity and alkaline phosphodiesterase activity of plasma membrane are higher in the three resistant sublines than in the parental cell line. We obtained a number of hybridomas producing antibodies to plasma membrane of an ACR-resistant subline of L5178Y cells. Among the syngeneic monoclonal antibodies, one was found by agglutination tests to react with the ACR-resistant cell line, but not significantly with the parental and ADM-, BLM-and MCR-resistant cell lines. Fluorographs of [14C] leucine-labeled ACR-resistant cells demonstrates two protein bands of 230 K and 20 K daltons, which are precipitated by the monoclonal antibody. The former seems to be specific to the ACR-resistant cells. Based on the results so far obtained, the 230 K protein may be related to the drug resistance and may be TATA (tumor-associated transplantation antigen). The results suggest that isolation of drug-resistant neoplastic cells is a novel method of finding TATA.
Insights
Researchers studied drug resistance in cancer cells, finding that altered cell membranes and a specific 230 K protein are key. This discovery may help identify new tumor-associated transplantation antigens for cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Context:
- Anticancer agents exhibit selective toxicity primarily due to distribution and metabolism.
- Drug resistance in refractory cancers like gastric and lung cancer is a significant clinical challenge.
- Understanding mechanisms of acquired resistance is crucial for developing new therapeutic strategies.
Purpose:
- To investigate the mechanisms of drug resistance in murine T-lymphoblastoma L5178Y cell sublines.
- To identify molecular markers associated with resistance to adriamycin (ADM), aclarubicin (ACR), and bleomycin (BLM).
- To explore the potential of drug-resistant cells in identifying tumor-associated transplantation antigens (TATA).
Summary:
- Selected cell sublines resistant to ADM, ACR, or BLM showed decreased drug influx and increased efflux, leading to lower drug retention.
- Resistant sublines exhibited altered plasma membrane properties, including increased glycoprotein-synthesizing and alkaline phosphodiesterase activity.
- A monoclonal antibody identified a specific 230 K protein band in ACR-resistant cells, potentially linked to drug resistance and TATA.
Impact:
- Identified a novel 230 K protein potentially associated with adriamycin, aclarubicin, and bleomycin resistance in cancer cells.
- Suggests that isolating drug-resistant cancer cells is a viable method for discovering tumor-associated transplantation antigens.
- Provides insights into mechanisms of drug resistance and potential targets for novel cancer therapies.