Posted by rob on September 14, 2005 under Uncategorized | 
Talpaz M, Rakhit A, Rittweger K, O’Brien S, Cortes J, Fettner S, Hooftman L, Kantarjian H
Clin Cancer Res. 2005 Sep 1; 11(17): 6247-55
PURPOSE: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-alpha-2a in which IFN-alpha is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c. drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous leukemia (CML) who were previously treated with IFN-alpha to evaluate the effect of sustained exposure to IFN on patients with CML. EXPERIMENTAL DESIGN: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was given once weekly by s.c. injections starting at a dose of 270 microg/wk to a maximum dose of 630 microg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 microg/wk in combination with two different schedules of low-dose cytarabine (1-beta-D-arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-IFN in these patients. RESULTS: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 mug/wk. With the addition of ara-C, the DLT was reached at 540 microg/wk. The safety profile was similar to that of unmodified IFNs. Of 27 patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration (C(max)) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 microg/wk, with no further increases in C(max) at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained at close to peak value throughout the dosing interval. The mean +/- SD area under the serum concentration-time curve (AUC) calculated after the first dose also increased from 1,022 +/- 694 to 3,343 +/- 2,728 ng hour/mL as dose was increased from 270 to 450 microg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with C(max), the AUC did not increase at higher dose levels. The maximum induction (E(max)) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline values as the dose was increased from 270 to 540 microg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing over 6 months.CONCLUSION: Pegasys provided a significant advantage over standard IFN-alpha by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients provides a promise for further investigation in combination with new agents like imatinib.
Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia.
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Brueggemeier SB, Wu D, Kron SJ, Palecek SP
Biomacromolecules. 2005 Sep-Oct ; 6(5): 2765-75
We describe the development of an array-based assay for the molecular level detection of tyrosine kinase activity directly from cellular extracts. Glutathione S-transferase-Crkl (GST-Crkl) fusion proteins are covalently immobilized into polyacrylamide gel pads via copolymerization of acrylic monomer and acrylic-functionalized GST-Crkl protein constructs on a polyacrylamide surface. The resulting hydrogels resist nonspecific protein adsorption, permitting quantitative and reproducible determination of Abl tyrosine kinase activity and inhibition, even in the presence of a complex cell lysate mixture. Half-maximal inhibition (IC(50)) values for imatinib mesylate inhibition of GST-Crkl (SH3) phosphorylation by v-Abl in a purified system and Bcr-Abl within a K562 cell lysate were determined to be 1.5 and 20 muM, respectively. Additionally, the protein-acrylamide copolymer arrays detected CML cell levels as low as 15% in a background of Bcr-Abl(-) leukemic cells and provided the framework for the parallel evaluation of six tyrosine kinase inhibitors. Such a system may have direct application to the detection and treatment of cancers resulting from upregulated tyrosine kinase activity, such as chronic myeloid leukemia (CML). These findings also establish a basis for screening tyrosine kinase inhibitors and provide a framework on which protein-protein interactions in other complex systems can be studied.
Protein-acrylamide copolymer hydrogels for array-based detection of tyrosine kinase activity from cell lysates.
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Wodarz D, Komarova NL
Semin Cancer Biol. 2005 Sep 7;
Small molecule inhibitors target specific metabolic pathways in tumor cells and are a promising class of drugs for the treatment of cancers. The best known example is the treatment of chronic myeloid leukemia (CML) with Gleevec. This is a small molecule inhibitor of the Bcr-Abl kinase which has been shown to drive the initiation and progression of CML. While treatment of early stage CML with Gleevec has been quite successful, later stages of the disease (blast crisis) are not successfully treated due to the emergence of drug resistant cells. It is therefore important to understand the principles according to which drug resistant cells evolve, so that we can design treatment strategies which aim to prevent the rise of resistant cells. Such evolutionary dynamics can be studied with mathematical models, and this article reviews such an approach. We address three specific questions: (i) Do resistant cells emerge before or after the start of therapy? (ii) How does the turnover rate of cancer cells influence the evolution of drug resistant cells? (iii) Can combination therapy be used to prevent drug resistance? We apply our model to the treatment of CML with Gleevec, in order to demonstrate how this mathematical framework can be applied to the treatment of a specific cancer with small molecule inhibitors.
Emergence and prevention of resistance against small molecule inhibitors.
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Cortes J, Kantarjian H
J Clin Oncol. 2005 Sep 10; 23(26): 6316-24
The treatment of chronic myeloid leukemia has changed dramatically in the last few years. Stem-cell transplantation and the use of interferon alfa had already offered the possibility of complete and durable cytogenetic responses, improving the survival over that expected with conventional chemotherapy. The introduction of imatinib mesylate has started the era of molecular therapy with remarkable results including complete cytogenetic responses in up to 90% of patients and major molecular responses in most. However, some patients, particularly those treated in the advanced stages, may develop resistance to imatinib. Thus there has been interest in developing new agents that would not only help patients for whom imatinib is ineffective or intolerable, but that could also be combined with the intention of eliminating all evidence of disease. Several approaches are being pursued. These include new and more potent tyrosine kinase inhibitors that may not be affected by the most common mutations seen in the clinic. Some of these agents also inhibit Src-related kinases that may play a role in the development of resistance to imatinib. Other agents are directed at downstream or alternative pathways in leukemic cells, exploring potential synergy with imatinib. Another approach is to pursue an immune modulation that might eliminate small amounts of residual disease. Many of these agents are already showing promising results in the clinic. This manuscript reviews some of these agents, particularly those for which clinical data are already available.
New targeted approaches in chronic myeloid leukemia.
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Graff JJ, Sathiakumar N, Macaluso M, Maldonado G, Matthews R, Delzell E
J Occup Environ Med. 2005 Sep ; 47(9): 916-932
OBJECTIVE:: This study evaluated the association between exposure to several chemicals and mortality from lymphohematopoietic cancer (LHC) among 16,579 synthetic rubber industry workers who were followed up from 1943 to 1998. METHODS:: Poisson regression analyses examined LHC rates in relation to butadiene, styrene, and DMDTC exposure. Models provided maximum likelihood estimates of the relative rate for the contrast between categories of one agent, adjusting for other agents and for additional potential confounders. RESULTS:: Cumulative exposure to 1,3-butadiene was associated positively with all leukemia (relative rates of 1.0, 1.4, 1.2, 2.9, and 3.7, respectively, for exposures of 0, >0 to
Chemical Exposures in the Synthetic Rubber Industry and Lymphohematopoietic Cancer Mortality.
