Methotrexate leukemia

Thymidylate synthase Methotrexate Leukemia response, colorectal cancer response... 

Panetta JC, Wall A, Pui CH, Rolling MV, Evans WE. Methotrexate intracellular disposition in acute lymphoblastic leukemia a mathematical model of gamma-glutamyl hydrolase activity. Clin Cancer Res 2002 8 2423-9. 

Panetta JC, Yanishevski Y, Pui CH, Sandlund JT, Rubnitz J, Rivera GK et al. A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2002 50 419-28. 

C, cytarabine ASP, asparaginase CALCB, Cancer and Leukemia Croup B CNS, central nervous system CTX, cyclophosphamide DEX, dexamethasone DNR, daunorubicin DOX, doxorubicin IT, intrathecal captopurine MTX, methotrexate PRED, prednisone TG, thioguanine VCR, vincristine. 

The prevalence of CNS disease at diagnosis of AML ranges from 5% to 30% in various treatment series. Features associated with the risk of CNS leukemia include hyperleukocytosis, monocytic or myelomonocytic leukemia (FAB M4 or M5), and young age. In most cases, intrathecal cytarabine with or without methotrexate and systemic high-dose cytarabine provide adequate CNS prophylaxis.3 Results from studies have shown that patients with CNS disease at diagnosis can be cured with intrathecal therapy alone without the use of cranial irradiation.11... 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

JM Weissbrod, RK Jain, FM Sirotnak. Pharmacokinetics of methotrexate in leukemia cells Effect of dose and mode of injection. J Pharmacokin Biopharm 6 487-503, 1978. 

Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that postsurgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. 

III. A nine-year-old boy is diagnosed with acute lymphoblastic leukemia. He is maintained on methotrexate. A recent platelet count is below normal, and a stool guaiac is 4+. Which of the following agents should be administered to counteract methotrexate toxicity ... 

High-dose methotrexate in pediatric acute lymphoblastic leukemia impact of ABCC2 polymorphisms on plasma concentrations. Clinical Pharmacology and Therapeutics, 80, 468—476. 

Bums, C. P., Luttenegger, D. G., Dudley, D. T., Buettner, G. R., and Spector, A. A., 1979, Effect of modification of plasma membrane fatty add composition on fluidity and methotrexate transport in L1210 murine leukemia cells. Cancer Res. 39 1726-1732. 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

In stark contrast, the second historically significant anti-cancer drug, methotrexate, originated from nutritional research. The observation that the vitamin folic acid stimulated prohferation of acute lymphoblastic leukemia (ALL) cells in children prompted synthesis of folate analogues. In the late 1940s methotrexate became the first drug to induce remissions in children with ALL [11]. 

Methotrexate is used to treat severe lymphatic leukemia, choriocarcinoma, non-Hodgkin s lymphoma, bone carcinoma, as well as head, neck, breast, and lung tumors. Synonyms of this drug are farmitrexate, ledertrexate, ematexate, maxtrex, folex, mexate, and others. 

Other Methotrexate also is indicated as an antineoplastic chemotherapy in various types of cancers and acute lymphocytic leukemia. 

Folic acid antagonists are of historical interest as a representative of this group, i.e. methotrexate, produced the first, although temporary, remissions in leukemia and the first cure of a solid tumor, choriocarcinoma. 

Clinical applications include childhood acute lymphoblastic leukemia, choriocarcinoma, osteosar-com, non-Hodgkin s lymphoma and Burkitt s lymphoma. However methotrexate is also frequently used as an immunosuppressant in diseases such as psoriasis, rheumatoid arthritis and others. 

The existence of the blood-brain barrier is an important consideration in the chemotherapy of neoplastic diseases of the brain or meninges. Poor drug penetration into the CNS has been a major cause of treatment failure in acute lymphocytic leukemia in children. Treatment programs for this disease now routinely employ craniospinal irradiation and intrathecally administered methotrexate as prophylactic measures for the prevention of relapses. The testes also are organs in which inadequate antitumor drug distribution can be a cause of relapse of an otherwise responsive tumor. 

Other routes of administration can be employed in certain situations. Methotrexate and cytarabine are given intrathecally or intraventricularly to prevent relapses in the meninges in acute lymphocytic leukemia and to treat carcinomatous meningitis. Thiotepa and bleomycin have been administered by intravesical instillation to treat early bladder cancers. Fluorouracil can be applied topically for certain skin cancers. 

Methotrexate is part of curative combination chemotherapy for acute lymphoblastic leukemias, Burkitt s lymphoma, and trophoblastic choriocarcinoma. It is also useful in adjuvant therapy of breast carcinoma in the palliation of metastatic breast, head, neck, cervical, and lung carcinomas and in mycosis fungoides. 

Methotrexate is one of the few anticancer drugs that can be safely administered intrathecally for the treatment of meningeal metastases. Its routine use as prophylactic intrathecal chemotherapy in acute lymphoblastic leukemia has greatly reduced the incidence of recurrences in the CNS and has contributed to the cure rate in this disease. Daily oral doses of methotrexate are used for severe cases of the nonneoplastic skin disease psoriasis (see Chapter 41), and methotrexate has been used as an immunosuppressive agent in severe rheumatoid arthritis. 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with an anthracycline agent, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and the lymphomas and has no known activity against other tumors. It has been used intrathecally in the treatment of meningeal leukemias and lymphomas as an alternative to methotrexate. 

Answer Immediately arrange for an evaluation of the CSF. If the CSF reveals leukemic cells, you can consider administering methotrexate 12 mg in-trathecally every day for 4 days. With such a regimen, subsequent evaluations of the CSF often indicate no leukemic cells present. The headaches and balance problems typically disappear. Six months later, most patients show no evidence of leukemia. 

Bokkering J, DamenF, Huylscher Met al. Biochemical evidence for synergistic combination treatment with methotrexate and 6-mercaptopurine in childhood acute lymphoblastic leukemia. Haematol Blood Transfus 1990 33 110-117. 

Dervieux T, Hancock ML, Evans WE et al. Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine. Leukemia 2002 16 209-212. 

Dervieux T, Hancock ML, Pui CH et al. Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia. Clin Pharmacol Ther 2003 73 506-516. 

Beach BJ, Woods WG, Howell SB. Influence of cotrimoxazole on methotrexate pharmacokinetics in children with acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1981 3 115-119. 

Schmiegelow K, Glomstein A, Kristinsson J et al. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol 1997 19 102-109. 

Balis FM, Holcenberg JS, Poplack DG et al. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia a joint Childrens Cancer Group and Pediatric Oncology Branch study. Blood 1998 92 3569-3577. 

Sehmiegelow K, Sehroder H, Gustafsson G et al. Risk of relapse in ehildhood aeute lymphoblastie leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenanee... 

Schmiegelow K, Bjork O, Glomstein A et al. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. JC/rri Onco/2003 21 1332-1339. 

Key Words Acute lymphoblastic leukemia pharmacogenetics single nucleotide polymorphisms outcome English folate pathway methotrexate... 

Chiusolo P, Reddiconto G, Casorelli I et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol 2002 13 1915-1918. 

Shimasaki N, Mori T, Samejima H et al. Effects of methylenetetrahydrofolate reductase and reduced folate earrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. JPediatr Hematol Oncol 2006 28 64-68. 

Laverdiere C, Chiasson S, Costea 1 et al. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. B/oorf 2002 100 3832-3834. 

Dihydrofolate reductase is competitively inhibited by methotrexate, a folic acid analogue used to effect the remission of acute leukemia in children. 

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