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Factors that influence the penetration of methotrexate through solid tissue
1Department of Medicine, Ontario Cancer Institute and University of Toronto, Ontario, Canada.
International Journal of Cancer
|January 10, 2001
Summary
Drug penetration into solid tumors is limited. Studies show methotrexate penetration is poor, but higher folic acid levels or acidic conditions may improve drug delivery, enhancing anticancer therapy.
Area of Science:
- Pharmacology
- Oncology
- Biomedical Engineering
Background:
- Limited drug penetration through tumor tissue hinders effective solid tumor treatment.
- Methotrexate is a key anticancer drug whose efficacy can be limited by poor tumor penetration.
Purpose of the Study:
- To investigate the penetration of radiolabeled methotrexate through multicellular layers (MCL) of cancer cells.
- To identify factors influencing methotrexate penetration and cellular uptake.
Main Methods:
- Utilized radiolabeled methotrexate to study penetration through MCL of murine EMT-6 and human MCF-7 cells.
- Assessed penetration across semiporous teflon membranes under various conditions (folic acid, pH, hypoxia, folinic acid).
Main Results:
- Methotrexate penetration was significantly limited, reaching only about 25% of that through a blank membrane after 6 hours.
- High concentrations of folic acid (>0.1 mM) and acidic conditions enhanced tissue penetration by decreasing cellular uptake.
- Hypoxic conditions and folinic acid (leucovorin) did not affect methotrexate penetration or uptake.
Conclusions:
- Methotrexate primarily penetrates solid tumors via the extracellular space, suggesting limited distribution.
- Strategies involving folic acid or altered pH may improve methotrexate tissue penetration and enhance anticancer efficacy.
- Further research can optimize drug delivery for improved solid tumor treatment.