Transport and intracellular retention of folates
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there are 2 major transporters that move folate and its analogues into cells
- REDUCED FOLATE CARRIER (RFC):
- ubiquitous low affinity, high capacity system that represents the major folate transport system
- becomes extremely important at pharmacological folate/antifolate concentrations
- transports LEUCOVORIN > FOLATE > METHOTREXATE
- reduced expression or mutation of the RFC is a source of the primary resistance to low-dose METHOTREXATE exhibited by some cancer cells and some bacteria
- because the cancer cells have decreased function of the RFC, LEUCOVORIN can be used to rescue the normal cells following administration of the extremely high doses of methotrexate needed to kill the resistant cancer/bacterial cells
- LEUCOVORIN RESCUE is effective in both cancer and antibacterial chemotherapy
- REDUCED FOLATE CARRIER (RFC):
Reduced expression or mutation of the reduced folate carrier (RFC) is a cause of primary resistance to low doses of folate inhibitors (such as METHOTREXATE). Both cancer cells and bacteria (esp. Pneumocystis jirovecii - an AIDS-associated infection) can exhibit resistance. High doses of MTX are used to overcome this resistance, and subsequent administration of LEUCOVORIN allows normal cells with functional RFC to bypass the drug-induced inhibition of dihydrofolate reductase. This is the fundamental principle underlying rescue therapy. |
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- FOLATE RECEPTOR:
- high affinity, low capacity system found only in specific tissues (kidney, lung, choroid plexus and placenta)
- requires internalization (the process is called potocytosis) à slow
- operates to transport folates when they are present at very low concentrations
- transports FOLATE >>> METHOTREXATE
- overexpressed in some leukemias as well as gynecological and epithelial cancers (e.g., ovarian carcinoma, mesothelioma and choriocarcinoma), making these neoplasms more sensitive to folate inhibitors (compared to other cancers)
- being investigated as a tumour cell marker for targeted drug development
LEUCOVORIN RESCUE
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high doses force METHOTREXATE uptake via the FOLATE RECEPTOR, allowing intracellular concentrations to reach therapeutic levels, even in cells with reduced expression or RFC
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normal cells can be rescued by administration of LEUCOVORIN, since it can cross via the RFC in those cells
- see the discussion under antineoplastics
POLYGLUTAMINATION
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once inside the cell, folates (esp. PEMETREXED and PRALATREXATE) are polyglutamated by the enzyme folylpolyglutamate synthase (FPGS)
- this process is required for biological activity, and it:
- facilitates retention (increases intracellular concentrations)
- increases affinity for folate-dependent enzymes (including thymidylate synthase)
- cancer cells are more capable of the polyglutamation à selective toxicity