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Expression of a multidrug resistance gene in human cancers
L J Goldstein1, H Galski, A Fojo
1Division of Cancer Biology and Diagnosis, National Cancer Institute, Bethesda, MD 20892.
Abstract:
Many cancers have been cured by chemotherapeutic agents. However, other cancers are intrinsically drug resistant, and some acquire resistance following chemotherapy. Cloning of the cDNA for the human MDR1 gene (also known as PGY1), which encodes the multidrug efflux protein P-glycoprotein, has made it possible to measure levels of MDR1 RNA in human cancers. We report the levels of MDR1 RNA in greater than 400 human cancers. MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties. MDR1 RNA levels were occasionally elevated in other untreated cancers, including neuroblastoma, acute lymphocytic leukemia (ALL) in adults, acute nonlymphocytic leukemia (ANLL) in adults, and indolent non-Hodgkin's lymphoma. MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma. Many types of drug-sensitive and drug-resistant tumors, including NSCLC and melanoma, contained undetectable or low levels of MDR1 RNA. The consistent association of MDR1 expression with several intrinsically resistant cancers and the increased expression of the MDR1 gene in certain cancers with acquired drug resistance indicate that the MDR1 gene contributes to multidrug resistance in many human cancers. Thus, evaluation of MDR1 gene expression may prove to be a valuable tool in the identification of individuals whose cancers are resistant to specific agents. The information may be useful in designing or altering chemotherapeutic protocols in these patients.
Insights
The human MDR1 gene, encoding P-glycoprotein, is often elevated in drug-resistant cancers, both intrinsic and acquired. Measuring MDR1 RNA levels can help identify resistant tumors and guide chemotherapy protocols.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemotherapy is effective for many cancers, but intrinsic or acquired drug resistance remains a significant challenge.
- The human MDR1 gene (PGY1) encodes P-glycoprotein, a key mediator of multidrug resistance.
- Measuring MDR1 RNA levels offers a potential method to assess drug resistance in various cancers.
Purpose of the Study:
- To quantify MDR1 RNA levels in over 400 human cancers.
- To investigate the association between MDR1 expression and intrinsic or acquired drug resistance.
- To evaluate the utility of MDR1 gene expression analysis in clinical oncology.
Main Methods:
- Cloning of the human MDR1 gene cDNA.
- Quantification of MDR1 RNA levels in a large cohort of human cancers.
- Analysis of MDR1 RNA levels in relation to cancer type, intrinsic resistance, and acquired resistance post-chemotherapy.
Main Results:
- Elevated MDR1 RNA levels were frequently observed in intrinsically drug-resistant tumors (e.g., colon, kidney, liver, pancreas, NSCLC).
- Increased MDR1 RNA was also noted in certain untreated leukemias and lymphomas, and in cancers relapsing after chemotherapy (e.g., ALL, ANLL, breast cancer).
- Many drug-sensitive cancers, including NSCLC and melanoma, showed low or undetectable MDR1 RNA levels.
Conclusions:
- MDR1 gene expression is consistently associated with intrinsic multidrug resistance in human cancers.
- Increased MDR1 expression correlates with acquired drug resistance following chemotherapy.
- Evaluation of MDR1 gene expression may aid in identifying resistant cancers and optimizing chemotherapeutic strategies.