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Effects of Folinic Acid on Hepatoma Cells Containing Methotrexate Polyglutamates

Center for Laboratories and Research, New York State Department of Health, Albany, New York 12201

¹ Recipient of NIH Grant CA 25933 awarded by the National Cancer Institute, USPHS, Department of Health and Human Services. To whom requests for reprints should be addressed.

The effects of folinic acid on a toxic pulse exposure of cultured hepatoma cells to methotrexate (4-amino-10-methylpteroylglutamic acid) is reported. Inclusion of folinic acid (5-formyl-5,6,7,8-tetrahydropteroylglutamic acid) (10 µM) with the 2-hr pulse of methotrexate (10 µM) nearly completely prevents the uptake and -glutamylation of methotrexate and prevents toxicity. Addition of folinic acid after methotrexate results in a partial rescue that is time and concentration dependent. Restoration of cell growth in the presence of increasing amounts of folinic acid is accompanied by a concentration-dependent elevation in tritium release from [5-³H]deoxyuridine. In the absence of folinic acid, the release of tritium from [5-³H]deoxyuridine remains inhibited for three days after exposure to methotrexate, which can be related to the cellular formation and retention of methotrexate polyglutamates. Following the 2-hr pulse of methotrexate, the cellular pool consists of 70% polyglutamates of which the predominant species has three glutamate residues (4-NH₂-10-CH₃PteGlu₃). When methotrexate is removed from medium, following the pulse, unmetabolized methotrexate rapidly leaves the cells, and 4-NH₂-10-CH₃PteGlu₃ is converted to methotrexate polyglutamates containing four to six glutamate residues. Addition of folinic acid after the methotrexate pulse prevents the conversion of 4-NH₂-10-CH₃PteGlu₃ to the higher-chain-length derivatives and causes a reduction in the total methotrexate cell pools over the next 48 hr. These results suggest that the effects of folinic acid on methotrexate polyglutamates may play a role in the rescue of cells containing these derivatives.

Received 5/10/82. Accepted 11/ 1/82.

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