ALL , CML

Uses AML, ALL, CML Action Purine-based antimetabolite (substitutes for natural purines interfering w/ nucleotide synth) Dose 2-3 mg/kg/d X in severe renal/hepatic impair Caution [D, -] Contra Resistance to mercaptopurine Disp Tabs SE X BM (leucopenia/thrombocytopenia), NA /D, anorexia, stomatitis, rash, hyperuricemia, rare hepatotox Interactions t Bleeding W/ anticoagulants, NSAIDs, salicylates, thrombolytics EMS t Effects of anticoagulants/salicylates/ NSAIDs T risk of Infxn OD May cause NA, hypotension, and diaphoresis symptomatic and supportive... 

Cytarabine Inhibits DNA chain elongation, DNA synthesis and repair inhibits ribonucleotide reductase with reduced formation of dNTPs incorporation of cytarabine triphosphate into DNA AML, ALL, CML in blast crisis Nausea and vomiting, myelosuppression with neutropenia and thrombocytopenia, cerebellar ataxia... 

Imatinib. Chronic myelogenous leukemia (CML) results from a genetic defect in the hematopoietic stem cells of the bone marrow. Nearly all CML patients possess the Philadelphia chromosome. It results from translocation between chromosomes 9 and 22 of the c-abl protooncogene, leading to the hybrid bcr-abl fusion gene on chromosome 22. The recombinant gene encodes a tyrosine kinase mutant with unregulated (constitutive), enhanced activity that promotes cell proliferation. Imatinib is a tyrosine kinase inhibitor that specifically affects this mutant but also interacts with some other kinases. It can be used orally in Philadelphia chromo-some-positive CML. 

Figure 39-14 Schematic representation of the BCR (22q 11) and ABL (9q34) genes involved in the t(9 22), which is characteristic of all CMLs and a subset of ALLs. The centromeric (cen) and teiomeric (tel) directions are indicated.The relative positions of the major breakpoint duster (M-BCR), the minor breakpoint duster (m-6CR), and the micro breakpoint duster regions (ft-BCR) are shown. The previously used alternative nomenclature for the BCR and ABL exons is included where relevant. In panel A, the exons of the BCR genes are depicted in black rectangles, and those of the ABL genes are depicted in white rectangles. In panel B, the configuration and varieties of the BCR-ABL chimeric fusions seen in CML are shown. In the lower part of panel B, the configuration and varieties of the BCR-ABL fusions seen in ALL are shown. The el-a2 transcript is most commonly detected in t(9 22)-positive ALL, while the b3-a2 and b2-a2 fusions are the most commonly detected in CML...

Let us begin by considering the stability of homogeneous solutions and/or initial-conditions i.e. by considering the stability of a simple-diffusive CML when cri(O) = a for all sites i , where a is a fixed point of the local logistic map F(cr) = acr(l—cr). Following Waller and Kapral [kapral84], we first recast equations 8.23 and 8.24... 

It turns out that, in the CML, the local temporal period-doubling yields spatial domain structures consisting of phase coherent sites. By domains, we mean physical regions of the lattice in which the sites are correlated both spatially and temporally. This correlation may consist either of an exact translation symmetry in which the values of all sites are equal or possibly some combined period-2 space and time symmetry. These coherent domains are separated by domain walls, or kinks, that are produced at sites whose initial amplitudes are close to unstable fixed points of = a, for some period-rr. Generally speaking, as the period of the local map... 

Table 8.6 traces the evolution of the approximating CA rules as e increases from 0 to 1 for 2 < s < 3. We see that as e increases, only 7 of the 32 possible rules are actually visited. Nonetheless, even at this crude first order approximation, a remnant of the CML s transition to spatiotemporal intermittency remains. In particular, there is a threshold value of e, = 2 — 4/s, that acts as a boundary point below which the approximating CA-rule is simple-periodic (class 1 or 2) and above which it is complex (class 3 or 4). The surprising fact is not that the CML s transition appears to bo approximated by the CA-rule path - after all, allowing for finite-length computer words, the CML itself is essentially just a very-high order CA... 

Imatinib (Gleevec) TKI Bcr-Abl, c-Kit, PDGFR, Lck Inhibition of kinase activity - ATP-competitive, binding to an inactive conformation CML ALL GIST DFSP MDS/MPD ASM HES/CEL... 

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. 

The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxic-ities in older patients. The adverse prognostic factor, the Philadelphia chromosome, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.17 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR-ABL tyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone,... 

There have been significant advances in the treatment of CML. The success of therapy depends in part on the clinical phase of the disease. Nearly all patients with CML are treated initially with imatinib. Hydroxyurea may be used after diagnosis to rapidly reduce high white blood cell (WBC) counts and to prevent complications associated with large numbers of circulating neutrophils. Imatinib also can reduce peripheral WBC counts over... 

Chronic myeloid leukemia (CML) occurs when there is a translocation of chromosomes 9 and 22 (also called Philadelphia translocation—a chromosomal abnormality). These two different chromosomes break off and reattach on the opposite chromosome. A consequence is that the activity of the Bcr-Abl gene, which encodes the enzyme tyrosine kinase, is turned on all the time. With this heightened activity, high levels of white blood cells are produced in the bone marrow. 

This work has shown that PTFE films can be deposited using RF magnetron sputtering over a range of deposition conditions, with power densities varying from 0.3 to 1.13 W/cml In all cases adherent films were produced showing no delamination even after extended exposure times (out to 16,000 h). The rate of deposition was found to increase in a near linear manner with deposition power, as can be seen in Figure 19.2. 

While imatinib is efficacious in treating Philadelphia chromosome positive CML, it is not as effective a treatment for patients with Philadelphia chromosome positive ALL [47]. As a prelude to clinical investigation, AMN107 was studied for its effect on Bcr-Abl positive ALL cell lines [48]. In prohferation and Bcr-Abl phosphorylation assays with two patient-derived ALL cell hnes, namely Z-119 and Z-181, AMN107 was 30-40-fold more potent than imatinib. 

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