Leukemic

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

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. 

For patients with leukemia, the transfer of siRNA-based strategies into clinical applicability will certainly be both frustrating and time-consuming and many hurdles still have to be overcome in order to realize the therapeutic potential of siRNAs. Efficient delivery of siRNA into the leukemic stem cell and their unknown influence of the patient s immune system are the most challenging issues that need to be addressed. 

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. 

Chang, C.C., Konno, S., Wu, J.M. (1991). Enhanced expression of heat shock protein and mRNA synthesis by type I interferon in human HL-60 leukemic cells. Biochem Inti. 24, 369-377. 

Zee-Cheng KY, Cheng CC. Common receptor-complement feature among some anti-leukemic compounds. J Pharm Sci 1970 59 1630-4. 

The expression of many of these molecules has been studied during various stages of differentiation of normal neutrophils and also of corresponding leukemic cells employing molecular biology techniques (eg, measurements of their specific mRNAs). For the majority, cDNAs have been isolated and sequenced, amino acid sequences deduced, genes have been localized to specific chromosomal locations, and exons and intron sequences have been defined. Some important proteinases of neutrophils are listed in Table 52-12. 

Amir, H. et ah. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells, Nutr. Cancer, 33, 105, 1999. 

The initial treatment for acute leukemias is called induction. The purpose of induction is to induce a remission, a lack of identifiable leukemic cells in the bone marrow or peripheral blood with light microscopy. This definition may change as more sensitive techniques come into play. 

O The acute leukemias are diseases of bone marrow resulting from aberrant proliferation of hematopoietic precursors. The hallmark of these malignancies is the leukemic blast cell, a visibly immature and abnormal cell in the peripheral blood that often replaces the bone marrow and interferes with normal hematopoiesis. These blast cells proliferate in the marrow and inhibit normal cellular elements, resulting in anemia, neutropenia, and thrombocytopenia. Leukemia also may infiltrate other organs, including the liver, spleen, bone, skin, lymph nodes, and central nervous system (CNS). Virtually anywhere there is blood flow, the potential for extramedullary (outside the bone marrow) leukemia exists. 

Chloromas (localized leukemic deposits named after their color) may be seen, especially in the periorbital regions and as skin infiltrates. 

Flow cytometric evaluation of bone marrow and peripheral blood to characterize the type of leukemia, as well as to detect specific chromosomal rearrangements. The bone marrow at diagnosis usually is hypercellular, with normal hematopoiesis being replaced by leukemic blasts. The presence of greater than 20% blasts in the bone marrow is diagnostic for AML. 

In both children and adults with ALL, clinical trials have identified several risk factors that correlate with outcome (Table 92-5). Prognostic features include age, WBC count, cytogenetic abnormalities, ploidy, leukemic cell immunophe-notype, and degree of initial response to therapy.7 When these factors are combined, they predict groups of patients with varying degrees of risk for treatment failure. 

Patients often present with bone pain secondary to expansion of the marrow cavity from leukemic infiltration. 

CNS prophylaxis is necessary in any treatment regimen for ALL At diagnosis, the incidence of CNS disease is less than 10%, but it increases to 50% to 75% after 1 year in patients without CNS prophylaxisA The justification for CNS prohylaxis is based on two clinical findings. First, many chemotherapeutic agents do not cross the blood-brain barrier easily. Second, the CNS is a frequent sanctuary for leukemia, and undetectable leukemic cells are present in the CNS in many patients at the time of diagnosis.6... 

Relapse is the recurrence of leukemic cells at any site after remission has been achieved. Most relapses occur during treatment or within the first 2 years of its completion. The bone marrow is the most frequent site of relapse in both ALL and AML and accounts for 90% or more of relapses. Extramedullary relapse, such as the CNS and the testes, while once common, has decreased to 5% or less because of effective prophylaxis.21... 

Cumock AP, Sotsios Y, Wright KL, Ward SG. Optimal chemotactic responses of leukemic T cells to stromal cell-derived factor-1 requires the activation of both class IA and IB phosphoinositide 3-kinases. J Immunol 2003 170(8) 4021 4030. 

The DNA forms stable complexes with doxorubicin (Adriamycin, ADR) and daunorubicin (DNR). Doxorubicin and DNR, although structurally similar, show distinctly different properties ADR is more toxic and active than DNR in the treatment of various human solid tumors the apparent binding affinity of ADR to DNA is about 1.8 times higher than that of DNR to DNA. Trouet et al. [229] found the ADR-DNA complex to be more active than ADR, DNR, or DNR-DNA in subcutaneously inoculated leukemic mice, whereas the DNR-DNA complex showed the highest... 

FG King, RL Dedrick. Physiological model for the pharmacokinetics of 2 -deoxyco-formycin in normal and leukemic mice. J Pharmacokin Biopharm 9 519-534, 1981. 

Ali AM, Umar-Tsafe N, Mohamed SM, et al. Apopotosis induction in CEM-SS T-lymphoblastic leukemic cell line by goniothalamin. J Biochem Mol Biol Biophys 2001 5 253-261. 

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

Williams, A.B. and Jacobs, R.S. (1993) A marine natural product, patellamide D, reverses multidrug resistance in a human leukemic cell line. Cancer Letters, 71, 97. 

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