Lymphoblastic leukemia

Although the compounds were isolated in quantities of only a few milligrams per kilogram of cmde plant leaves, extensive work on a variety of animal tumor systems led to eventual clinical use of these bases, first alone and later in conjunction with other materials, in the treatment of Hodgkin s disease and acute lymphoblastic leukemia. Their main effect appears to be binding tightly to tubuHn, the basic component of microtubules found in eukaryotic cells, thus interfering with its polymerization and hence the formation of microtubules required for tumor proliferation (82). 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with anthracyclines, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and lymphomas and has marginal activity against other tumors. Myelosuppres-sion is a major toxicity, as is severe bone marrow hypoplasia nausea and mucositis may also occur. 

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

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. 

In order to evaluate the in vitro antitumor activity of the prodrugs, compounds 20 and 21 were incubated at varied concentrations with human T-lineage acute lymphoblastic leukemia MOLT-3 cells in the presence or absence of ImM of PGA. The data from the cell proliferation assays are presented in Fig. 5.15. 

Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma... 

B-cell acute lymphoblastic leukemia CD19, CD20, CD10, and CD22... 

Gokbuget N, Hoelzer D. Recent approaches in acute lymphoblastic leukemia in adults. Rev Clin Exp Hematol 2002 6 114-141. 

Pui CH. Acute lymphoblastic leukemia. Pediatr Clin North Am 1997 44 831-846. 

Pui CH, Relling MV, Campana D, et al. Childhood acute lymphoblastic leukemia. Rev Clin Exp Hematol 2002 6 161-180. 

Cancers Multiple myeloma Non-Hodgkin s lymphoma Hodgkin s disease Acute myeloid leukemia Neuroblastoma Germ cell tumors Acute myeloid leukemia Acute lymphoblastic leukemia Chronic myeloid leukemia Myelodysplastic syndrome Myeloproliferative disorders Non-Hodgkin s lymphoma Hodgkin s disease Chronic lymphocytic leukemia Multiple myeloma... 

Acute lymphoblastic leukemia High-grade non-Hodgkin s lymphoma (i.e. Burkitt s) Intermediate risk... 

Prophylaxis and treatment of hyperuricemia associated with tumor lysis syndrome. ALL, acute lymphoblastic leukemia AML, acute myelogenous leukemia IV, intravenous. (Data from refs. 32 and 33.)... 

ALL Acute lymphoblastic leukemia acute lymphocytic BID Twice daily (bis in die)... 

Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capde-ville R, Talpaz M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome N. Engl J Med 2001 344 1084-1086. 

Clinical Use and Toxicity of 6-MP in Childhood Acute Lymphoblastic Leukemia... 

Schmiegelow K, Bruunshuus I. 6-Thio-guanine nucleotide accumulation in red blood cells during maintenance chemotherapy for childhood acute lymphoblastic leukemia, and its relation to leukopenia. Cancer Chemother Pharmacol 1990 26 288-292. 

Relling MV, Hancock ML, Boyett JM et al. Prognostic importance of 6-mercap-topurine dose intensity in acute lymphoblastic leukemia. Blood 1999 93 2817-2823. 

Dibenedetto SP, Guardabasso V, Ragu-sa R et al. 6-Mercaptopurine cumulative dose a critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1994 11 251-258. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

McLeod HL, Reeling MV, Liu Q et al. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 1995 85 1897-1902. 

Stanulla M, Schrappe M, Brechlin AM et al. Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia a case-control study. Blood 2000 95 1222-1228. 

Chen CL, Liu Q, Pui CH et al. Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia. Blood 1997 89 1701-1707. 

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine dmgs, such as 6-mercaptopurine (6-MP), 6-thioguanine and azathioprine, to inactive metabolites [29-32]. Thiopurines form part of the routine treatment for patients with acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune diseases such as SLE and Crohn s disease, and are used as an immunosuppressant following organ transplantation. 

McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukaemia 2000 14 567-572. 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

Later on, the importance of xanthine oxidase as the producer of reoxygenation injury was questioned at least in the cells with low or no xanthine oxidase activity. Thus, it has been shown that human and rabbit hearts, which possess extremely low xanthine oxidase activity, nonetheless, develop myocardial infractions and ischemia-reperfusion injury [9], However, recent studies supported the importance of the xanthine oxidase-catalyzed oxygen radical generation. It has been showed that xanthine oxidase is partly responsible for reoxygenation injury in bovine pulmonary artery endothelial cells [10], human umbilical vein and lymphoblastic leukemia cells [11], and cerebral endothelial cells [12], Zwang et al. [11] concluded that xanthine dehydrogenase may catalyze superoxide formation without conversion to xanthine oxidase using NADH instead of xanthine as a substrate. 

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 ... 

Jak-2 Persistent activation Recurrent pre-B acute lymphoblastic leukemia (pre-B ALL) IL-6 dependent multiple myeloma... 

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