Methotrexate rescue therapy with

Plasma methotrexate concentrations as a therapeutic guide to high-dose methotrexate therapy with leucovorin rescue continue leucovorin until plasma methotrexate concentrations are <5 X 10 M (see dosage)... 

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

The fifth tetrahydrofolate compound is 5-formyl THF (folinicacid, citrovorum factor). This compound is not a coenzyme, but it can be converted to any of the active coenzyme forms. It is administered after treatment with the dihydrofolate reductase inhibitor, methotrexate (F ig. 8.47), as a form of rescue therapy. Because it already is in the reduced tetrahydrofolate form, it does not need dihydrofolate reductase to become an active coenzyme. 

Methotrexate exerts significant antiproliferative effects on the bone marrow therefore, complete blood counts should be monitored. Folinic acid (leucovorin) can be used to rescue patients with hematologic crises caused by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is necessary but may not be adequate to identify early hepatic fibrosis in patients receiving chronic methotrexate therapy. Liver biopsy is recommended when the cumulative dose reaches 1-1.5 g. A baseline hver biopsy also is recommended for patients with increased... 

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 administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

Krause AS, Weihrauch MR, Bode U, Fleischhack G, Elter T, Heuer T, Engert A, Diehl V, Josting A. Carboxy-peptidase-G2 rescue in cancer patients with delayed methotrexate elimination after high-dose methotrexate therapy. Leuk Lymphoma 2002 43(11) 2139-43. 

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