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Drug Transport and Resistance Mechanisms
Research Guide
What is Drug Transport and Resistance Mechanisms?
Drug Transport and Resistance Mechanisms refer to the biological processes, primarily involving ATP-dependent transporters like P-glycoprotein and ABC transporters, that enable drug efflux from cells and contribute to multidrug resistance in cancer chemotherapy.
This field examines over 88,681 papers on mechanisms such as ATP-dependent transporters, P-glycoprotein, bile acids, ABC transporters, and drug efflux pumps in cancer multidrug resistance. Key studies highlight the role of these transporters in reducing intracellular drug accumulation, as shown in "Multidrug resistance in cancer: role of ATP–dependent transporters" by Gottesman et al. (2002). Research also covers nuclear receptors, metabolic regulation, and effects on intestinal barrier function.
Topic Hierarchy
Research Sub-Topics
P-glycoprotein Mediated Multidrug Resistance
This sub-topic investigates P-glycoprotein (ABCB1) function in cancer drug efflux, substrate specificity, and inhibition strategies. Researchers study its overexpression in tumors and clinical correlations.
ABC Transporters in Cancer Chemotherapy
Focuses on diverse ABC transporters (e.g., ABCC1-12) contributing to multidrug resistance beyond P-gp, including their regulation and pharmacological targeting. Studies span solid tumors and leukemias.
Nuclear Receptors in Drug Transporter Regulation
Researchers explore how PXR, CAR, and FXR regulate ABC transporter expression in response to xenobiotics and bile acids. This includes transcriptional mechanisms and drug-drug interactions.
Drug Efflux Pumps in Intestinal Barrier
This sub-topic examines ABC transporters' roles in intestinal absorption, bioavailability, and barrier function, influenced by bile acids and metabolism. Studies use in vitro and pharmacokinetic models.
ATP-Dependent Transporters in Tumor Stem Cells
Investigates how transporters confer resistance in cancer stem cells, linking to dormancy, metastasis, and relapse. Research integrates single-cell omics and functional assays.
Why It Matters
Drug transport and resistance mechanisms directly impact cancer chemotherapy outcomes by enabling tumor cells to expel drugs via efflux pumps, leading to treatment failure. Gottesman et al. (2002) in "Multidrug resistance in cancer: role of ATP–dependent transporters" detail how ATP-dependent transporters like P-glycoprotein reduce drug efficacy across multiple cancer types. Higgins (1992) in "ABC Transporters: From Microorganisms to Man" describes ABC transporters' broad role in drug resistance, affecting clinical treatments. Dean et al. (2005) in "Tumour stem cells and drug resistance" link these mechanisms to cancer stem cells, explaining relapse after therapy. In oncology, overcoming these barriers improves patient survival, as contextualized by cancer incidence data in Jemal et al. (2006) "Cancer Statistics, 2006", which reported estimates for new cases and deaths in the US.
Reading Guide
Where to Start
"Multidrug resistance in cancer: role of ATP–dependent transporters" by Gottesman et al. (2002) provides a foundational overview of efflux mechanisms central to the field, making it ideal for initial reading.
Key Papers Explained
Gottesman et al. (2002) "Multidrug resistance in cancer: role of ATP–dependent transporters" establishes the core role of P-glycoprotein and ABC transporters in cancer resistance, which Higgins (1992) "ABC Transporters: From Microorganisms to Man" extends by detailing their evolutionary conservation and broad function. Dean et al. (2005) "Tumour stem cells and drug resistance" builds on this by linking transporters to stem cell persistence. Veber et al. (2002) "Molecular Properties That Influence the Oral Bioavailability of Drug Candidates" connects molecular design to overcoming transport barriers.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Current research emphasizes interactions between metabolic regulation, nuclear receptors, and transporters in intestinal barriers and cancer, as reflected in the 88,681 works. Zanger and Schwab (2013) "Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation" highlights genetic impacts on metabolism linked to transport. No recent preprints or news available indicate focus remains on established mechanisms.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Molecular Properties That Influence the Oral Bioavailability o... | 2002 | Journal of Medicinal C... | 7.7K | ✕ |
| 2 | Lead- and drug-like compounds: the rule-of-five revolution | 2004 | Drug Discovery Today T... | 5.8K | ✕ |
| 3 | Multidrug resistance in cancer: role of ATP–dependent transpor... | 2002 | Nature reviews. Cancer | 5.4K | ✕ |
| 4 | Cancer Statistics, 2006 | 2006 | CA A Cancer Journal fo... | 5.3K | ✓ |
| 5 | Structure and function of the blood–brain barrier | 2009 | Neurobiology of Disease | 4.9K | ✓ |
| 6 | Definition of drug resistant epilepsy: Consensus proposal by t... | 2009 | Epilepsia | 4.5K | ✕ |
| 7 | SREBPs: activators of the complete program of cholesterol and ... | 2002 | Journal of Clinical In... | 4.3K | ✓ |
| 8 | ABC Transporters: From Microorganisms to Man | 1992 | Annual Review of Cell ... | 4.0K | ✕ |
| 9 | Cytochrome P450 enzymes in drug metabolism: Regulation of gene... | 2013 | Pharmacology & Therape... | 3.9K | ✓ |
| 10 | Tumour stem cells and drug resistance | 2005 | Nature reviews. Cancer | 3.6K | ✕ |
Frequently Asked Questions
What role do ATP-dependent transporters play in multidrug resistance?
ATP-dependent transporters, such as P-glycoprotein, actively pump drugs out of cancer cells, reducing intracellular concentrations and causing resistance to multiple chemotherapy agents. Gottesman et al. (2002) in "Multidrug resistance in cancer: role of ATP–dependent transporters" explain this mechanism's centrality in cancer. This efflux prevents effective drug action despite adequate dosing.
How do ABC transporters contribute to drug resistance?
ABC transporters facilitate drug efflux across cell membranes in microorganisms and humans, conferring multidrug resistance. Higgins (1992) in "ABC Transporters: From Microorganisms to Man" outlines their structure and function in expelling diverse substrates. In cancer, they limit chemotherapy penetration into tumors.
What is the connection between tumor stem cells and drug resistance?
Tumor stem cells exhibit heightened drug resistance through enhanced transport mechanisms and quiescence. Dean et al. (2005) in "Tumour stem cells and drug resistance" describe how these cells survive chemotherapy and drive tumor regrowth. Targeting them requires overcoming efflux pumps like those in ABC families.
How do molecular properties affect oral drug bioavailability?
Reduced molecular flexibility and optimal polar surface area improve oral bioavailability of drug candidates. Veber et al. (2002) in "Molecular Properties That Influence the Oral Bioavailability of Drug Candidates" analyzed over 1100 compounds in rats, identifying key properties like low flexibility. These insights guide design of drugs resistant to transport-mediated clearance.
What factors influence blood-brain barrier transport?
The blood-brain barrier regulates drug entry via tight junctions and efflux transporters like P-glycoprotein. Abbott et al. (2009) in "Structure and function of the blood–brain barrier" detail its composition and role in excluding xenobiotics. This impacts CNS drug delivery in resistant conditions.
How is drug resistant epilepsy defined?
Drug resistant epilepsy is defined as failure of adequate trials of two tolerated antiepileptic drugs to achieve sustained seizure freedom. Kwan et al. (2009) in "Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies" provide this ILAE consensus. The definition aids research into transport-related resistance.
Open Research Questions
- ? How can inhibitors specifically target P-glycoprotein without affecting normal ATP-dependent transport?
- ? What structural modifications in ABC transporters enable broad substrate specificity in cancer cells?
- ? In what ways do tumor stem cells upregulate efflux pumps compared to differentiated cells?
- ? How do nuclear receptors regulate expression of drug transporters in intestinal barriers?
- ? What metabolic pathways interact with bile acids to modulate ABC transporter activity in multidrug resistance?
Recent Trends
The field encompasses 88,681 papers with sustained interest in ABC transporters and P-glycoprotein, as evidenced by high citations for Gottesman et al. at 5431 and Higgins (1992) at 3984.
2002Growth data over 5 years is unavailable, but persistent citations to works like Dean et al. with 3622 underscore ongoing relevance of stem cell resistance.
2005No recent preprints or news in the last 12 months reported.
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