Antineoplastics
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Antineoplastics Hyperphenylalani naemia in children with acute lymphoblastic leukaemi a: clinical study It has been previously reported that patients with acute lymphoblastic leukaemia receiving chemotherapy develop neurological disease . However, the suggestion that methotrexate, a dihydrofolate reductase inhibitor, inhibits the biosynthesis of tetrahydrobiopterin at the dihydropteridine reductase stage has not been verified. The development of hyperphenylalaninaemia was observed in a number of paediatric patients with acute lymphoblastic leukaemia who were treated with chemotherapy comprising methotrexate, asparaginase, cyclophosphamide, doxorubicin , daunorubicin, cytarabine, th ioguanine , mercaptopurine, vincristine and etoposide. Plasma phenylalanine levels were between 150 and 1400 in these patients, and they were noted to be more depressed and apathetic compared with patients with normal plasma phenylalanine levels. A loading test of tetrahydrobiopterin 10 mg/ kg was conducted in 2 patients. Plasma phenylalanine levels decreased at 4 and 8 hours, respectively, f rom 1422 to 121 and 1 51 in 1 patient and fro m 491 to 382 and 230 in the other. Urinary pterin in all patients studied was indicative of dihydropteridine reductase deficiency. High plasma phenylalanine corresponded with the finding that > 70% of biopterin + neopterin was biopterin. In the CSF , biopterin l evels were elevated, homova ni llic acid levels were normal and 5-hydroxyindolacetic acid was depressed. Although dihydropteridine reductase activity in erythrocytes was normal, patients had received multiple infusions. The data suggested '_ , , that in patients with ALL [acute lymphoblastic leukaemia}, hyperphenylalaninemia is induced by inhibition of DHPR [dihydropteridine reductase} activity', The refore , 'we believe that administration of tetrahydrobiopterin during the distinct phases of chemotherapy may prevent the development of hyperphenylalaninemia and thus relieve the neurologic symptoms'. Blau N. Curtlus HC. Klera l L. Leupold O . Kohne E Hyperphenylalanlnemla caused by dlhydropterldine reductase deficiency In children receiving chemolherapy for acute lymphoblaStiC leukemia Journal of Pedia trics 115 661 ·662, Oct 1989 '42 Hyperphenylalaninaemia in children with acute lymphoblastic leukaemia: follow-up comment Hyland K, Smith I, Heales SJR. Hyperphenylalalnemla caused by dlhydroplerldlne reductase deficiency In child ren receiv ing chemotherapy for acute lymphoblas ti c l eukemia Reply Journal of Pediatrics 115: 662, Oct 1989 "" Thrombotic microangiopathy: case report Fields SM, lindley CM ThrombotiC mlcroanglopathy associated wi th chemotherapy: case report and review of the lit erature. OI CP Annal s of Pharmacotherapy 23 582·588, Jul·Aug 1989 [63 references) 600
Transcript of Antineoplastics
Antineoplastics Hyperphenylalaninaemia in children with acute lymphoblastic leukaemia: clinical study
It has been previously reported that patients with acute lymphoblastic leukaemia receiving chemotherapy develop neurological disease. However, the suggestion that methotrexate, a dihydrofolate reductase inhibitor , inhibits the biosynthesis of tetrahydrobiopterin at the dihydropteridine reductase stage has not been verified.
The development of hyperphenylalaninaemia was observed in a number of paediatric patients with acute lymphoblastic leukaemia who were treated with chemotherapy comprising methotrexate, asparaginase, cyclophosphamide, doxorubicin , daunorubicin, cytarabine, th ioguanine, mercaptopurine, vincristine and etoposide. Plasma phenylalanine levels were between 150 and 1400 ~molfL in these patients, and they were noted to be more depressed and apathetic compared with patients with normal plasma phenylalanine levels.
A loading test of tetrahydrobiopterin 10 mg/kg was conducted in 2 patients. Plasma phenylalanine levels decreased at 4 and 8 hours, respectively, from 1422 to 121 and 151 ~mol/L , in 1 patient and from 491 to 382 and 230 ~mol/L in the other. Urinary pterin in all patients studied was indicative of dihydropteridine reductase deficiency. High plasma phenylalanine corresponded with the finding that > 70% of biopterin + neopterin was biopterin. In the CSF , biopterin levels were elevated, homovani llic acid levels were normal and 5-hydroxyindolacetic acid was depressed. Although dihydropteridine reductase activity in erythrocytes was normal, patients had received multiple infusions .
The data suggested '_ , , that in patients with ALL [acute lymphoblastic leukaemia}, hyperphenylalaninemia is induced by inhibition of DHPR [dihydropteridine reductase} activity ', Therefore, 'we believe that administration of tetrahydrobiopterin during the distinct phases of chemotherapy may prevent the development of hyperphenylalaninemia and thus relieve the neurologic symptoms'.
Blau N. Curt lus HC. Klera l L. Leupold O . Kohne E Hyperphenylalanlnemla caused by dlhydropterldine reductase deficiency In children receiving chemolherapy for acute lymphoblaStiC leukemia Journal of Pedia trics 115 661 ·662, Oct 1989 '42
Hyperphenylalaninaemia in children with acute lymphoblastic leukaemia: follow-up comment Hyland K, Smith I, Heales SJR. Hyperphenylalalnemla caused by dlhydroplerldlne reductase deficiency In child ren receiving chemotherapy for acute lymphoblas tic leukemia Reply Journal of Pediatrics 115: 662, Oct 1989 ""
Thrombotic microangiopathy: case report Fields SM, lindley CM ThrombotiC mlcroanglopathy associated wi th chemotherapy: case report and review of the literature. OICP Annals of Pharmacotherapy 23 582·588, Jul·Aug 1989 [63 references) 600
