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Leucovorin

Leucovorin

Question
My sister is 49 years old and has breast cancer. She underwent quadrantectomy and they found cancer cells in three lymph nodes. She is scheduled for chemotherapy and then radiation. Someone in her support group referred to a drug called a "rescue" drug. Is there any information you can provide on that drug? Does it have to do with the blood cells and the effect that chemotherapy has on them?


Answer
John Han-Chih Chang, MD and Kenneth Blank, MD, OncoLink Editorial Assistants, responds:

Thank you for your interest and question.

The drug or chemotherapeutic agent to which they were referring is leucovorin. To explain what it is attempting to "rescue," we have to understand the other chemotherapeutic agents' mechanisms of action. The types of chemotherapy agents with which leucovorin are utilized are methotrexate (MTX) and 5-fluorouracil (5-FU). They are classified as anti-metabolites.

Methotrexate is an inhibitor of dihydrofolate reductase (DHFR), which maintains intracellular folates in the reduced form. Reduced folates in cells are used for production of DNA building blocks (bases). Thus, if there is lack of reduced folates in cells, they would not be able to repair and create more DNA resulting in DNA strand breaks and fragmentation leading to dying cells. Because the rapidly dividing and growing cells in the body require more production and repair of DNA, they seem to be most affected by chemotherapy. Cancer, bone marrow, hair follicles and gastrointestinal lining cells are just a few of the cell types that are rapidly proliferating and seem to be most affected by the anti-cancer drugs (basis of chemotherapy).

5-FU is phosphorylated into metabolites, which inhibit thymidylate synthetase (TS) by forming a complex with covalent bonds to TS. TS also functions in preparing bases to be utilized for DNA synthesis. Thus, 5-FU disrupts DNA repair and production of rapidly proliferating cells also. Of note, in times of low reduced folate levels, the complex dissociates much quicker.

With that background being given, leucovorin is a reduced folate that is utilized with the two aforementioned chemotherapeutics. With high-dose MTX, leucovorin is given to "rescue" the gastrointestinal lining and bone marrow cells from MTX toxicity. Usually, the blood level of MTX is measured and an appropriated dose of leucovorin is given to benefit the gastrointestinal lining and bone marrow and not effect MTX's toxic effect on the cancer. For 5-FU, having a reduced folate actually prolongs the binding of 5-FU's metabolites to the TS enzyme. Thus, using leucovorin actually increases the duration of 5-FU's cytotoxic function.