Chromosomal position

Inhibition of hematopoietic growth factors Imatinib (Glivec ) is applied to treat chronic myeloid leukemia in Philadelphia-chromosome positive patients. In these patients, translocation of parts of chromosomes 9 and 22 results in the expression of a fusion protein with increased tyrosine kinase activity, called Bcr-Abl. Imatinib is a small Mw inhibitor selective for the tyrosine kinase activity of Bcr-Abl. Thereby, it inhibits the Bcr-Abl induced cell cycle progression and the uncontrolled proliferation of tumor cells. 

Figure 3.3 Comparison of array CGH among DNA extracted from fresh tissue, FFPE tissue by heating protocol or nonheating protocol for two human tissue samples of metastatic carcinoma in lymph node (a-c), and undifferentiated non-small cell carcinoma (d-f). Array CGH hybridization genomic profiles show ratio values representing relative copy number of single BACs. A good result is scored as 1.0 that indicates a low standard deviation for gains (>0.2), normal (0.0), or losses (<-0.2). In these two cases, fresh samples show best score as 2, both FFPE tissue samples show identical score of 3. Each spot represents the average of three replicates. Clones are ordered by chromosomal position as numbers at the bottom (x axis) of each picture. The y axis is the log2 ratio of test reference intensity. Provided by Sandy DeVries from Dr. Frederic Waldman s Lab at UCSF.

D3. Dhingra, K., Talpaz, M., Riggs, M. G., Eastman, P. S., Zipf, T., et al.. Hybridization protection assay A rapid, sensitive, and specific method for detection of Philadelphia chromosome-positive leukemias. Blood 77, 238-242 (1991). 

H2. Herman, A., Heisterkamp, N., von Lindem, M., Bootsman, D., and Grosveld, G., Unique fusion of bcr and c-abl genes in Philadelphia chromosome-positive acute lymphoblastic leukemia. Cell (Cambridge, MA) 51, 33-40 (1987). 

Namciu SJ, Blochhnger KB, Eoumier RE (1998) Human matrix attachment regions insulate transgene expression from chromosomal position effects in Drosophila melanogaster. Mol Cell Biol 18 2382-2391... 

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. 

Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia after ima-tinib treatment and for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. The overall mean terminal half-life of dasatinib is 3-5 hours. Adverse events included mild to moderate diarrhea, peripheral edema, and headache. Neutropenia and myelosuppression were common toxic effects. 

Indications Treatment of chronic hepatitis C, hairy-cell leukemia and AIDS-related Kaposi s sarcoma, as well as for the treatment of chronic phase, Philadelphia chromosome-positive chronic myelogenous leukemia (CML)... 

Hofmann WK, de Vos S, Elashoff D et al. Relation between resistanee of Philadelphia-chromosome-positive acute lymphoblastie leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles a gene-expression study. Lancer 2002 359 481 86. 

Quintas-Cardama A, Kantarjian H, Jones Det al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure, fi/ooct 2007 109 497M99. 

Kantarjian H, Giles F, Wunderle L et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. NEngl JMed2006 354 2542-2551. 

Snyder, D.S., Wu, Y., McMahon, R., Yu, L., Rossi, J.J. and Forman, S.J. (1997) Ribozymemediated inhibition of a Philadelphia chromosome-positive acute lymphoblastic leukemia cell line expressing the pi 90 bcr-abl oncogene. Biol. Blood Marrow Transplant., 3, 179-186. 

Advice for treatment decisions based on specific genetic conditions were found in four Pis, namely that prolastin (a 1-proteinase inhibitor) is not indicated in patients with certain otl -antitrypsin deficiency phenotypes, trastuzumab indicated only in patients with overexpression of the HER2 protein, tretinoin, and imatinib are to be given only in patients with either a specific subtype of acute myelogenous leukemia or Philadelphia chromosome-positive chronic myeloid leukemia, respectively. 

The relationships between nilotinib plasma concentration and clinical efficacy (or toxicity) have not been studied yet. Irrespective of nilotinib PK-PD per se, Saglio et al. [72] showed that nilotinib at a dose of either 300 or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome-positive CML. At 12 months, the rates of major molecular response for nilotinib were nearly twice that observed for imatinib. The rates of complete cytogenetic response by 12 months were also significantly higher for nilotinib than for imatinib [72], No data have been published for nilotinib concentration-toxicity relationships nor plasma target values to be achieved for optimal clinical response. 

Hazarika M et al (2008) Tasigna for chronic and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res 14 5325-5331... 

Neviani P, Santhanam R, Oaks JJ, Hiring AM, Notari M, Blaser BW, et al. FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia. J. Clin. Invest. 2007 117 2408-2421. 

Kantarjian HM, O Brien S, Smith TL, Rios MB, Cortes J, Beran M, Koller C, Giles FJ, Andreeff M, Kornblau S, Giralt S, Keating MJ, Talpaz M. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol 1999 17(l) 284-92. 

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