Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity

Abstract

Kratak sadr`aj: Primena metotreksata (MTX) u viso kim dozama i/ili intratekalno u terapiji malignih obo ljenja poput akutne limfoblasti~ne leukemije (ALL) povezana je sa pojavom blagih ili te{kih oblika neuro toksi~nosti. Patogeneza neurotoksi~nosti nije u potpu nosti razja{njena, ali se va`na uloga pripisuje biohe mijskim promenama folatnog i metiltransfernog meta boli~kog puta za koje se smatra da su uzrokovane dejstvom MTX. Opisujemo slu~aj odrasle pacijen tkinje na terapiji recidiva ALL sa simptomima hroni~ne leukoencefalopatije najverovatnije uzrokovane primenom MTX. U cilju procene folatnog i metil-transfernog puta u cere brospinalnoj te~nosti (CST) pacijentkinje merene su koncentracije 5-metiltetrahidrofolata (5-metil-THF), S-adenozilmetionina (SAM) i S-adenozilhomocisteina (SAH). Tri uzorka CST su dobijena lumbalnom punkcijom u periodu od ~etiri meseca. Koncentracije su merene pomo}u validiranih bioana liti~kih metoda zasnovanih na primeni HPLC sa ultraljubi~astom i fluorescentnom detekcijom. Rezultati su pokazali dvostruko sni`enje koncentracije 5-metil-THF (29.3-31.8 nmol/L) u pore|enju sa referentnim vrednostima u svim uzor cima, dok su koncentracije SAM bile pet puta manje u dva uzorka (5-34.2 nmol/L). Koncentracije SAH su bile u rasponu 7.5-14.3 nmol/L. Na{a pacijentkinja je imala izra`ene promene u folatnom i metil-transfernom metaboli~kom putu koje uka zuju na to da biohemijske promene ovih metaboli~kih puteva za koje se smatra da su uzrokovane dejstvom MTX mogu igrati va`nu ulogu u razvoju leuko encefalopatije.Klju~ne re~i: metotreksat, cerebrospinalna te~nost, 5-metiltetrahidrofolat, S-adenozilmetionin, neurotoksi~nost Summary: Intrathecal and/or high-dose intravenous administration of methotrexate (MTX) in the treatment of malignancies such as acute lymphoblastic leukaemia (ALL) has been associated with cases of mild to severe neurotoxicity. The pathogenic mechanism of neurotoxicity is not clear, possibly MTX-associated biochemical alterations of the folate and methyl-transfer metabolic pathways play an important role. We report a case of an adult patient treated for ALL relapse with signs of chronic leukoencephalopathy associated with MTX administration. In order to assess alterations in the folate and methyl-transfer pathway we determined 5-methylte trahydrofolate (5-methyl-THF), S-adenosylmethi onine (SAM) and S-adenosylhomocysteine (SAH) in the cerebrospinal fluid (CSF) of the patient. Three CSF samples were obtained by lumbar punction within a four-month period. Concentrations of the metabolites were measured using validated bioanalytical methods based on HPLC with UV and fluorescence detection. The results showed two-fold lower 5-methyl-THF levels (29.3-31.8 nmol/L) in all obtained sam ples compared to reference values. SAM concentrations were even more than five-fold lower in two samples (5-34.2 nmol/L). SAH concentrations were in the range 7.5-14.3 nmol/L. Our patient had pronounced alterations in the folate and methyltransfer pathway which indicate that MTX-associated biochemical alter...

Urinary Activities of Proximal Tubule Enzymes in Neonates Treated with Gentamicin

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