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The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice
D R Johnson1, R A Finch, Z P Lin
1Department of Pharmacology and Developmental Therapeutics Program, Cancer Center and Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abstract:
Two major classes of plasma membrane proteins that actively extrude a wide range of structurally diverse hydrophobic amphipathic antineoplastic agents from cells, with different mechanisms of action, lead to multidrug resistance. To study the importance of these ATP-binding cassette transporters to the toxicity of cancer chemotherapy agents, we have used mice genetically deficient in both the mdr1a and mdr1b genes [mdr1a/1b(-/-) mice], the mrp1 gene [mrp1(-/-) mice], and the combined genes mdr1a/1b and mrp1 [mdr1a/1b(-/-), mrp1(-/-) mice] and embryonic fibroblasts derived from wild-type mice and from the three gene knockout animals. The consequences of export pump deficiencies were evaluated primarily using vincristine and etoposide. Mice deficient in the three genes, mdr1a/1b and mrp1, exhibited a 128-fold increase in toxicity to vincristine and a 3-5-fold increase in toxicity to etoposide; increased toxicity to embryonic fibroblast cells from triple knockout mice also occurred with vincristine and etoposide. Vincristine, which normally does not express toxicity to the bone marrow and to the gastrointestinal mucosa when used at therapeutic doses, caused extensive damage to these tissues in mdr1a/1b(-/-), mrp1(-/-) mice. The findings indicate that the P-glycoprotein and mrpl are compensatory transporters for vincristine and etoposide in the bone marrow and the gastrointestinal mucosa and emphasize the potential for increased toxicities by the combined inhibition of these efflux pumps.
Insights
Multidrug resistance in cancer chemotherapy involves plasma membrane transporters like P-glycoprotein and MRP1. Deficiencies in these efflux pumps significantly increase toxicity of agents such as vincristine and etoposide, particularly in sensitive tissues.
Area of Science:
- Pharmacology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, driven by plasma membrane proteins that efflux antineoplastic agents.
- ATP-binding cassette transporters, including P-glycoprotein (encoded by mdr1a/1b genes) and MRP1, play a crucial role in MDR.
Purpose of the Study:
- To investigate the contribution of specific efflux pumps (P-glycoprotein and MRP1) to the toxicity of chemotherapy drugs.
- To evaluate the compensatory roles of these transporters in drug resistance.
Main Methods:
- Utilized genetically modified mice lacking mdr1a/1b, mrp1, or both genes (triple knockout).
- Assessed drug toxicity using vincristine and etoposide in knockout mice and their derived embryonic fibroblasts.
- Examined tissue damage in bone marrow and gastrointestinal mucosa.
Main Results:
- Triple knockout mice (mdr1a/1b(-/-), mrp1(-/-)) showed a 128-fold increase in vincristine toxicity and a 3-5-fold increase in etoposide toxicity.
- Vincristine caused severe damage to bone marrow and gastrointestinal mucosa in triple knockout mice, tissues normally resistant at therapeutic doses.
- Embryonic fibroblasts from triple knockout mice exhibited increased sensitivity to both drugs.
Conclusions:
- P-glycoprotein and MRP1 act as compensatory transporters for vincristine and etoposide, particularly in the bone marrow and gastrointestinal tract.
- Combined inhibition of these efflux pumps has the potential to significantly increase chemotherapy-induced toxicities.