Folinic acid, methotrexate toxicity rescue

Similarly, folinic acid is used in conjunction with high-dose methotrexate for various cancers to minimise toxicity, when it is typically started 24 hours after methotrexate administration (folinic acid or leucovorin rescue). In this setting, the antidote effect is clearly influenced by the dose of folinate in relation to the dose of methotrexate, and the timing of foli-nate administration in relation to methotrexate administration. 

LEUCOVORIN. When leucovorin is administered after a large dose of methotrexate, the timing of tiie administration is outlined by tiie primary health care provider. It is essential that the leucovorin be given at tiie exact time ordered because tiie purpose of folinic acid rescue is to allow a high dose of a toxic drug to remain in tiie body for only a limited time... 

Leucovorin (folinic acid) - enzyme cofactor for thymidylate synthase rescues from methotrexate toxicity potentiates cytotoxicity of fluoro— pyrimidines -occasional nausea -skin rash -headache -rare allergic reactions... 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Methotexate is an antineoplastic folic add analogue that blocks the conversion of dihydrofolate (FHj) to tetrahydro-folate (FH4) by binding to dihydrofolate reductase (DHFR) enzyme. Folate is essential for the normal synthesis of purines and pyrimidines, and therefore DNA and RNA. In order for folate to function as a cofactor, it must be reduced to FH by DHFR. Methotrexate binds to DHFR, prevents the conversion of FH2 to FH4, and, consequently, inhibits purine and pyrimidine synthesis. The antimetabolites are considered cell cycle specific, with most activity for cells in the S (synthesis) phase. With high-dose methotrexate, leucovorin rescue is often used to prevent severe toxicity to normal body tissues. Leucovorin (folinic acid) is a reduced form of folate (similar to FH ) that does not require the use of DHFR. Leucovorin is transported into healthy cells and is utilized for DNA and RNA synthesis. Tumor cells tend to have impaired transport mechanisms and usually cannot use leucovorin. Leucovorin is usually started within 24 to 36 hours of high-dose methotrexate administration and continues until methotrexate serum levels are below nontoxic levels (0.1 to 0.05 mol/L). 

The rescue of normal, but not tumor, cells from methotrexate toxicity by folinic acid is partly explained by differences in membrane transport. For example, osteogenic sarcoma cells (which do not respond to conventional doses of methotrexate treatment) are not rescued by folinic acid administered after methotrexate, presumably owing to the absence of transport sites for folinic acid in the neoplastic cells. The therapeutic effects of administration of methotrexate and rescue with folinic acid are superior to those of methotrexate alone. Resistance to methotrexate can develop from increased activity of dihydrofolate reductase, synthesis of an enzyme having a lower affinity for the inhibitor, decreased transport of the drug into tumor cells, decreased degradation of the reductase, and genetic amplification of the gene for dihydrofolate reductase. 

Folinic acid (leucovorin) reduces the toxicity of methotrexate because it provides an active form of folate to normal (nonneo-plastic) cells, resulting in leucovorin rescue. Dexrazoxane is a free radical trapping agent that is thought to reduce the cardiotoxicity of anthracyclines (eg, doxorubicin). Mercaptoethanesulfonate (mesna), which inactivates acrolein, is available for protection against hemorrhagic cystitis in patients treated with cyclophosphamide and related drugs. 

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N -formyl FH ), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven useful in treating other cancers. 

When 2 patients with osteosarcoma, treated with high-dose methotrexate 12 give per course, were given ciprofloxacin 500 mg twice daily, either during or 2 days before the start of the methotrexate course, methotrexate elimination was delayed, resulting in raised serum levels, severe cutaneous toxicity and renal impairment. The first patient also had hepatic injury and haematological toxicity. Following increased folinic acid rescue, methotrexate levels normalised after several days. In earlier courses without ciprofloxacin in the first patient and subsequent courses without ciprofloxacin in the second patient, methotrexate elimination was normal. This preliminary report has subsequently been published in full. ... 

The picture is not totally clear but it seems possible that the previous use of cisplatin causes kidney damage that may not necessarily be detectable with the usual creatinine clearance tests, llie effect is to cause a marked reduction in the clearance of the methotrexate. The serum methotrexate levels of such patients should be closely monitored so that any delay in its clearance is detected early and folinic acid rescue therapy can be given. This appears to prevent serious toxicity. " ... 

Methotrexate is a close strnctnral analogne of folate and inhibits dihydrofolate reductase. This prevents the rednction of folate and dihydrofolate (DHF) to tetrahydrofolate (THF), which is the precursor of A ,lV -methylene THF. This is essential for dTTP and DNA synthesis. Unfortnnately, normal cells are also attacked by methotrexate. Folinic acid (A -formyl tetrahydrofolate) is an active form of folate that can be given after the start of methotrexate treatment to rescue normal cells from this drug toxicity. 

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