Administration Of STI571 Research Articles

Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease

Three loci that modify β-amyloid (Aβ) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the γ-secretase activity responsible for generating Aβ by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain Aβ deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of Aβ in both the blood and the brain, confirming brain Aβ's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to Aβ accumulation.

The Myofibroblastic Conversion of Peribiliary Fibrogenic Cells Distinct from Hepatic Stellate Cells Is Stimulated by Platelet-Derived Growth Factor During Liver Fibrogenesis

The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle α-actin–immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle α-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle α-actin, α1 (I) collagen mRNA, and PDGF receptor-β subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle α-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct–ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle α-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.

Chronic myelogenous leukemia in chronic phase.

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by genomic instability leading to its inevitable clinical evolution from an easily controlled chronic phase to a terminal blastic phase. The molecular abnormality responsible for this disease--BCR-ABL--and the critical biochemical aberrations resulting from it have been studied in depth. These discoveries have led to the development of a molecule, STI571, that specifically inhibits the abnormal kinase enzymatic activity exhibited by BCR-ABL. Early results of clinical trials using STI571 have shown responses even in blast crisis. There has also been striking hematologic and cytogenetic remission rates in patients with advanced chronic phase disease, with very little toxicity. It is our opinion that this molecule will revolutionize the treatment of CML. Furthermore, the path leading to its discovery will become a paradigm for cancer therapeutics. At the time of this writing, STI571 remains investigational (although it is widely believed that it will be approved for clinical use in the United States this year ). Although suggested therapy for a disease does not generally incorporate medications that are still investigational, in this case, the impact of a still investigational agent cannot be ignored. The current data suggest that STI571 will be the treatment of choice for patients with advanced or resistant chronic phase. To date, STI571 has not been studied adequately in untreated CML patients. Even so, it is our feeling that, based on its compelling success in patients with interferon-refractory and advanced disease and on its benign side effect profile, it will quickly become the front-line therapy for CML once it becomes available. Despite the ease of administration of STI571, patients should continue to be encouraged to participate in clinical studies so that several vital issues can be resolved: 1) the percentage of untreated CML patients who will eventually develop molecular remissions; 2) the proportion of patients in whom resistance to STI571 will emerge; 3) the optimum length of treatment; and 4) the impact on survival. Because interferon-alfa can also result in cytogenetic remissions, albeit in a small percent (less than 20%) of early chronic phase patients, it seems reasonable to suggest that patients who do not attain cytogenetic/molecular remissions with STI571 alone be treated with a combination of STI571 and interferon-alfa. Patients who are resistant to STI571 with or without interferon-alfa should undergo allogeneic hematopoietic cell transplant. Salvage therapy after transplant may include donor lymphocyte infusions, interferon-alfa, additional transplant, and perhaps STI571. Medications such as hydroxyurea appear destined to play a very limited role in CML. They may be used in the palliative treatment of older STI571-resistant patients or those without a transplant donor, although these patients may be best served by being considered for clinical trials of molecules, such as polyethylene glycol-interferon-alfa, on other novel agents.

Chronic myelogenous leukemia.

The treatment recommendations for chronic myelogenous leukemia (CML) are evolving rapidly. In the past year, pegylated interferon and STI571 (Gleevec, imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor, have become commercially available and non-myeloablative stem cell transplants continue to be refined. Clinicians and patients face a bewildering array of treatment options for CML. In this article Dr. Sawyer reviews the clinical results with STI571 and ongoing investigations into mechanisms of resistance to STI571. Given the newness of STI571, a practical overview on the administration of STI571 is presented by Drs. Druker and Ford, focusing on aspects such as optimal dose, management of common side effects, and potential drug interactions. The most recent data on interferon-based regimens are reviewed by Dr. Baccarani in the third section. In the last section Dr. Goldman presents recent results of allogeneic stem cell transplants, including the reduced intensity conditioning regimens. Lastly, the proposed place of each of these treatments in the management of CML patients is addressed to assist in deciding amongst treatment options for CML patients.