Long-term imatinib therapy promotes bone formation in CML patients

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2538-2547 ◽  
Author(s):  
Stephen Fitter ◽  
Andrea L. Dewar ◽  
Panagiota Kostakis ◽  
L. Bik To ◽  
Timothy P. Hughes ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Imatinib Therapy ◽  
Term Therapy ◽  
Bone Homeostasis ◽  
Bone Biopsies ◽  
Long Term Therapy

Imatinib inhibits tyrosine kinases important in osteoclast (c-Fms) and osteoblast (platelet-derived growth factor receptor [PDGF-R], c-Abl) function, suggesting that long-term therapy may alter bone homeostasis. To investigate this question, we measured the trabecular bone volume (TBV) in iliac crest bone biopsies taken from chronic myeloid leukemia (CML) patients at diagnosis and again after 2 to 4 years of imatinib therapy. Half the patients (8 of 17) showed a substantive increase in TBV (> 2-fold), after imatinib therapy, with the TBV in the posttreatment biopsy typically surpassing the normal upper limit for the patient's age group. Imatinib-treated patients exhibited reduced serum calcium and phosphate levels with hypophosphatemia evident in 53% (9 of 17) of patients. In vitro, imatinib suppressed osteoblast proliferation and stimulated osteogenic gene expression and mineralized-matrix production by inhibiting PDGF receptor function. In PDGF-stimulated cultures, imatinib dose-dependently inhibited activation of Akt and Crk-L. Using pharmacologic inhibitors, inhibition of PI3-kinase/Akt activation promoted mineral formation, suggesting a possible molecular mechanism for the imatinib-mediated increase in TBV in vivo. Further investigation is required to determine whether the increase in TBV associated with imatinib therapy may represent a novel therapeutic avenue for the treatment of diseases that are characterized by generalized bone loss.

INFLUENCE OF CHLOROPHENOXYISOBUTYRATE (CPIB) ON THYROID PARAMETERS

1969 ◽  
Vol 60 (2) ◽  
pp. 294-302 ◽  
Author(s):  
J. Mølholm Hansen
Keyword(s):  
Free Thyroxine ◽  
Term Therapy ◽  
Low Doses ◽  
Testosterone Metabolism ◽  
Pre Treatment ◽  
Long Term Therapy ◽  
Higher Doses

ABSTRACT Chlorophenoxyisobutyrate (CPIB) added to serum in vitro increases the quantity of dialysable thyroxine. The same effect can be obtained in vivo following large doses of the preparation. After low doses, increase in serum proteinbound iodine (PBI) is observed and with higher doses this increase is not observed, probably because of the thyroxine-displacing effect. Free thyroxine increases in practically all patients investigated. In long-term treated patients the alterations in dialysable thyroxine, serum proteinbound iodine and free thyroxine are transient; pre-treatment values being regained in the course of ½–4 months. 131I uptake in the thyroid gland is influenced irregularly and transiently possibly via inhibition of the thyrotrophin production in the hypophysis. The effect of CPIB on serum cholesterol appears, in long-term therapy, to be completely independent of the effect on these thyroid parameters. This observation is also supported by the fact that the 14C-testosterone metabolism is normal in patients receiving long-term therapy.

Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells

2001 ◽  
Vol 7 (1) ◽  
pp. 43-47 ◽  
Author(s):  
Samia Ragheb ◽  
Sarah Abramczyk ◽  
Deena Lisak ◽  
Robert Lisak
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Glatiramer Acetate ◽  
Mechanisms Of Action ◽  
Term Therapy ◽  
In Vitro Proliferation ◽  
Long Term Therapy

Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-b therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.

scholarly journals Enhanced Anticancer Activity of Nanoformulation of Dasatinib against Triple-Negative Breast Cancer by Reduced Metabolic Degradation

2021 ◽  
Author(s):  
Fatemah Bahman ◽  
Valeria Pittalà ◽  
Mohamed Haider ◽  
Khaled Greish
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Triple Negative Breast Cancer ◽  
Tyrosine Kinases ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Initial Response ◽  
Response To Chemotherapy

Triple negative breast cancer (TNBC) is the most aggressive breast cancer accounting for around 15% of identified breast cancer cases. TNBC, by lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is unresponsive to current targeted therapies. Existing treatment relies on chemotherapeutic treatment but, despite an initial response to chemotherapy, the inception of resistance and relapse is unfortunately common. Dasatinib is an approved second-generation inhibitor of multiple tyrosine kinases and literature data strongly support its use in the management of TNBC. However, dasatinib binds to plasma proteins and undergoes extensive metabolism through oxidation and conjugation. To protect dasatinib from fast pharmacokinetic degradation and to prolong its activity, it was encapsulated on poly(styrene-co-maleic acid) (SMA) micelles. The obtained SMA-dasatinib nanoparticles (NPs) were evaluated for their physicochemical properties, in vitro antiproliferative activity in different TNBC cell lines, and in vivo anticancer activity in a syngeneic model of breast cancer. Obtained results showed that SMA-dasatinib is more potent against 4T1 TNBC tumor growth in vivo compared to free drug. This enhanced effect was ascribed to the encapsulation of the drug protecting it from a rapid metabolism. Our finding highlights the often-overlooked value of nanoformulations in protecting its cargo from degradation. Overall, results may provide an alternative therapeutic strategy for TNBC management.

Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1931-1939 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi
Keyword(s):  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Growth Factor Receptor ◽  
Myeloproliferative Disorders ◽  
Hematologic Malignancies ◽  
Myeloid Metaplasia ◽  
Activating Mutations ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.

Effect of long-term therapy with an oral contraceptive on some aspects of hepatic lipid metabolism in vitro

1975 ◽  
Vol 24 (17) ◽  
pp. 1583-1588 ◽  
Author(s):  
Ira Weinstein ◽  
Richard Belitsky ◽  
Susan Seedman ◽  
Melvin J. Fregly ◽  
Terry N. Thrasher
Keyword(s):  
Lipid Metabolism ◽  
Oral Contraceptive ◽  
Term Therapy ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Long Term Therapy

Identification of the hemangioblast in postnatal life

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3203-3208 ◽  
Author(s):  
Elvira Pelosi ◽  
Mauro Valtieri ◽  
Simona Coppola ◽  
Rosanna Botta ◽  
Marco Gabbianelli ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Cell Subset ◽  
Growth Factor Receptor ◽  
Density Lipoprotein ◽  
Postnatal Life ◽  
Proliferative Potential

Abstract Postnatal CD34+ cells expressing vascular endothelial growth factor receptor 2 (KDR) generate hematopoietic or endothelial progeny in different in vitro and in vivo assays. Hypothetically, CD34+KDR+ cells may comprise hemangioblasts bipotent for both lineages. This hypothesis is consistent with 2 series of experiments. In the first series, in clonogenic culture permissive for hematopoietic and endothelial cell growth, CD34+KDR+ cells generate large hemato-endothelial (Hem-End) colonies (5% of seeded cells), whereas CD34+KDR− cells do not. Limiting-dilution analysis indicates that Hem-End colonies are clonally generated by single hemangioblasts. Sibling cells generated by a hemangioblast, replated in unicellular culture, produce either hematopoietic or Hem-End colonies, depending on the specific culture conditions. Identification of endothelial cells was based on the expression of VE-cadherin and endothelial markers and with lack of CD45 and hematopoietic molecules, as evaluated by immunofluorescence, immunocytochemistry, and reverse transcription–polymerase chain reaction. Furthermore, endothelial cells were functionally identified using low-density lipoprotein (LDL) uptake and tube-formation assays. In the second series, to evaluate the self-renewal capacity of hemangioblasts, single CD34+KDR+ cells were grown in 3-month extended long-term culture (ELTC) through 3 serial culture rounds—that is, blast cells generated in unicellular ELTC were reseeded for a subsequent round of unicellular ELTC. After 9 months, 10% blasts from tertiary ELTC functioned as hemangioblasts and generated macroscopic Hem-End colonies in clonogenic culture. These studies identified postnatal hemangioblasts in a CD34+KDR+ cell subset, endowed with long-term proliferative potential and bilineage differentiation capacity. Although exceedingly rare, hemangioblasts may represent the lifetime source/reservoir for primitive hematopoietic and endothelial progenitors.

scholarly journals Long-Term Azithromycin Therapy in Cystic Fibrosis Patients: A Study on Drug Levels and Sputum Properties

2004 ◽  
Vol 11 (2) ◽  
pp. 151-155 ◽  
Author(s):  
Ulrich Baumann ◽  
Malcolm King ◽  
Ernst M App ◽  
Shusheng Tai ◽  
Armin König ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Low Dose ◽  
Term Therapy ◽  
High Dose ◽  
Drug Levels ◽  
Diffuse Panbronchiolitis ◽  
Underlying Mechanisms

BACKGROUND:Following reports on the treatment of diffuse panbronchiolitis (DPB), recent studies demonstrate that long term therapy with azithromycin (AZM) is effective in cystic fibrosis (CF) patients. However, the underlying mechanisms remain uncertain. Some macrolides, including AZM, display inhibition of virulence factors and other antipseudomonal effects at subinhibitory levels in vitro.OBJECTIVES:Drug doses used for CF and DPB therapy were investigated to determine whether they achieve corresponding sputum drug levels in CF patients in vivo.METHODS:In an open, prospective study, 14 CF patients with chronic Pseudomonas aeruginosa airway infection received 250 mg AZM either daily ('high dose') or twice weekly ('low dose') for 12 weeks. Viscoelasticity of sputum was assessed by magnetic microrheology.RESULTS:AZM accumulated in sputum by two orders of magnitude over a period of four weeks. In the following steady state, median AZM concentrations in sputum were 9.5 µg/mL (0.6 to 79.3 µg/mL, interquartiles 1.4 to 33.4 µg/mL) and 0.5 µg/mL (range less than 0.1 [below detection level] to 5.2 µg/mL, interquartiles 0.2 to 1.4 µg/mL) in the high and low dose groups, respectively. Viscoelasticity improved in all patients but one.CONCLUSIONS:The findings suggest that antipseudomonal activity has to be considered among the potential mechanisms of macrolide therapy. Further, viscoelasticity may be a valuable parameter in future clinical trials.

scholarly journals Liposomal Lapatinib in Combination with Low-Dose Photodynamic Therapy for the Treatment of Glioma

2019 ◽  
Vol 8 (12) ◽  
pp. 2214 ◽  
Author(s):  
Carl Fisher ◽  
Girgis Obaid ◽  
Carolyn Niu ◽  
Warren Foltz ◽  
Alyssa Goldstein ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Cell Lines ◽  
Malignant Gliomas ◽  
Protoporphyrin Ix ◽  
Growth Factor Receptor ◽  
In Vivo Studies ◽  
Epidermal Growth

Background: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan®, has been studied previously with partial success in treating these tumours and extending lifetime. We aim to determine whether combining PDT using ALA-protoporphyrin IX (PpIX) with a liposomal formulation of the clinical epidermal growth factor receptor (EGFR) inhibitor, lapatinib, would increase the anti-tumour PDT efficacy. Methods: Lapatinib was given in vitro and in vivo 24 h prior to PDT and for 3–5 days following PDT to elicit whether the combination provided any benefits to PDT therapy. Live-cell imaging, in vitro PDT, and in vivo studies were performed to elucidate the effect lapatinib had on PDT for a variety of glioma cell lines and as well as GSC-30 neurospheres in vivo. Results: PDT combined with lapatinib led to a significant increase in PpIX accumulation, and reductions in the LD50 of PpIX mediated PDT in two EGFR-driven cell lines, U87 and U87vIII, tested (p < 0.05). PDT + lapatinib elicited stronger MRI-quantified glioma responses following PDT for two human glioma-derived tumours (U87 and GSC-30) in vivo (p < 0.05). Furthermore, PDT leads to enhanced survival in rats following treatment with lapatinib compared to lapatinib alone and PDT alone (p < 0.05). Conclusions: As lapatinib is approved for other oncological indications, a realization of its potential combination with PDT and in fluorescence-guided resection could be readily tested clinically. Furthermore, as its use would only be in acute settings, long-term resistance should not pose an issue as compared to its use as monotherapy.

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