In Vivo And Clinical Correlates Oncological Tangents

During the tenure of and even prior to the basic experiments of folate receptor function, we have studied the effects of antifolate therapy on folate stores in mice, rats, monkeys, and humans. This data have been reported over the past decade (72-74). In brief, repetitive, low-dose methotrexate results in a folate deficiency in the liver, red cells, and, of interest for this symposium, the brain. In particular, 1 yr of a "typical" methotrexate dose and schedule for treatment of children with acute lymphoblastic leukemia resulted in a 90% loss of folate in the brain of subhuman primates (73). Rats also showed a decrease in brain folate after only weeks of antifolate therapy, whether or not cranial radiation was given (72). Humans developed folate deficiency in liver and red cells as determined by biopsy and routine blood sampling (74). Concomitantly with our studies, the work of others (75) has revealed that therapy with methotrexate causes at least a transient increase in plasma homocysteine and we have recently found a striking increase (threefold to fivefold) in the amount of homocysteine in the CSF of children taking methotrexate, even with leucovorin (5-formyltetrahydrofolic acid) rescue as part of a planned treatment for acute lymphoblastic leukemia (4).

Because it is hypothesized that the folate receptor serves to maintain the CSF folate three to five times that of plasma, abnormalities in its synthesis or function may further compromise folate in the central nervous system (CNS), especially when antifolates are being taken. There is already a paradigm for abnormal synthesis: paroxysmal nocturnal hemoglobinuria (PNH) is an X-linked disease of the bone marrow in which GPI-anchored proteins are not synthesized. Consider the effects of blocking synthesis of or inhibiting the function of FR-a on the choroid plexus. Recently, a 60-yr-old woman presented to a neurologist with somnolence, ataxia, and signs of dementia. Routine studies revealed no diagnosis. She was found to have a normal plasma folate and homocysteine, but a markedly decreased CSF folate and elevated homocysteine. Treatment with folate and dextromethorphan, the latter a noncompetitive antagonist of the NMDA receptor triggered by homocysteine resulted in a neurological recovery. We postulated a failure to concentrate folate in the CSF as the basis for her physical findings. The cause remains unknown, but this case serves as an example that compartmentation of folate is important. Studies of the homozygous and heterozygous FR-a transgenic mice should yield a better understanding of folate homeostasis in the CSF (76).

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