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1.
Cancer Med ; 4(7): 995-1002, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25756742

ABSTRACT

Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar.


Subject(s)
Antineoplastic Agents/therapeutic use , Fusion Proteins, bcr-abl/genetics , Genes, abl , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Protein Kinase Inhibitors/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Drug Substitution , Female , Gene Expression Regulation, Neoplastic , Humans , Imatinib Mesylate/administration & dosage , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Protein Kinase Inhibitors/administration & dosage , Retreatment , Retrospective Studies , Time Factors , Transcription, Genetic , Treatment Failure , Treatment Outcome , Young Adult
2.
Am J Hematol ; 90(5): 429-33, 2015 May.
Article in English | MEDLINE | ID: mdl-25683327

ABSTRACT

The role of bosutinib as rescue treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth-line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression-free survival was 73%. Grade 3-4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.


Subject(s)
Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Compassionate Use Trials , Leukemia, Myeloid, Chronic-Phase/drug therapy , Nitriles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Quinolines/therapeutic use , Adult , Aged , Benzamides/therapeutic use , Dasatinib , Drug Resistance, Neoplasm , Female , Humans , Imatinib Mesylate , Leukemia, Myeloid, Chronic-Phase/enzymology , Leukemia, Myeloid, Chronic-Phase/mortality , Leukemia, Myeloid, Chronic-Phase/pathology , Male , Middle Aged , Piperazines/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Pyrimidines/therapeutic use , Retrospective Studies , Spain , Survival Analysis , Thiazoles/therapeutic use
3.
Am J Hematol ; 89(11): E206-11, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25059397

ABSTRACT

In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as "warning responses." In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR(4.5) ): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P = <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival.


Subject(s)
Benzamides/therapeutic use , Biomarkers, Tumor/blood , Drug Substitution , Fusion Proteins, bcr-abl/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Watchful Waiting , Benzamides/pharmacology , Clinical Trials, Phase III as Topic , Disease-Free Survival , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/antagonists & inhibitors , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Multicenter Studies as Topic , Piperazines/pharmacology , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/pharmacology , Randomized Controlled Trials as Topic , Survival Analysis , Treatment Outcome
4.
BMC Mol Biol ; 9: 65, 2008 Jul 18.
Article in English | MEDLINE | ID: mdl-18638371

ABSTRACT

BACKGROUND: this study set out to examine the effects of the treatment with 1,25-dihydroxyvitamin D3 (1,25D3) [150 IU/Kg (3.75 microg/Kg) one a day, for 15 days] to non-diabetic rats and in rats rendered diabetic by a single injection of streptozotocin [65 mg/kg]. RESULTS: treatment with 1,25D3 to non-diabetic rats did not affect the biochemical parameters measured in the plasma and urine of these animals. Likewise, insulin receptor expression in the kidney, liver, or adipose tissue and insulin-stimulated glucose transport in adipocytes from these animals were not affected either. Treatment with 1,25D3 to streptozotocin-induced diabetic rats did not correct the hyperglycemia, hypoinsulinemia, glycosuria or ketonemia induced by the diabetes, although it partially reversed the over-expression of the insulin receptor gene in the liver and adipose tissue, without altering the normal expression of this gene in the kidney. These effects were accompanied by a normalization of the number of insulin receptors without altering receptor affinity but improving the insulin response to glucose transport in adipocytes from these diabetic animals. Moreover, a computer search in the rat insulin receptor promoter revealed the existence of two candidate vitamin D response element (VDRE) sequences located at -256/-219 bp and -653/-620 bp, the first overlapped by three and the second by four AP-2-like sites. CONCLUSION: these genomic actions of 1,25D3 could represent beneficial effects associated with the amelioration of diabetes via mechanisms that possibly involve direct transcriptional activation of the rat insulin receptor gene. The candidate VDREs identified may respond to 1,25D3 via activation of the vitamin D receptor, although this remains to be investigated.


Subject(s)
Calcitriol/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/genetics , Insulin/metabolism , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Adipocytes/metabolism , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Base Sequence , Consensus Sequence , Diabetes Mellitus, Experimental/metabolism , Gene Expression/drug effects , Genomics , Glucose/metabolism , In Vitro Techniques , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Promoter Regions, Genetic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Wistar
5.
Neuropharmacology ; 54(6): 976-88, 2008 May.
Article in English | MEDLINE | ID: mdl-18371990

ABSTRACT

There is strong evidence that blocking CB1 receptors may reduce alcohol intake in alcohol-dependent individuals. However, there is still limited evidence that CB1 receptor antagonists may also be beneficial in the attenuation of alcohol withdrawal syndrome, even though alcohol withdrawal appears to be milder in CB1 receptor knockout mice. Here we have examined whether the CB1 receptor antagonist rimonabant (SR141716) can alleviate the behavioral symptoms and revert the neurochemical imbalance elicited by a 3-h interruption of chronic alcohol exposure (7.2% in the drinking water for 10 days) in male Wistar rats. Administration of rimonabant attenuated the strong anxiogenic traits of the animals that developed when regular alcohol intake was interrupted. This may reflect the correction of the GABA/glutamate imbalances developed by the animals that received rimonabant in various brain regions involved in emotional (e.g. prefrontal cortex) and motor (e.g. caudate-putamen and globus pallidus) responses. In addition, rimonabant also affected the dopamine deficits generated by alcohol abstinence in the amygdala and ventral-tegmental area, albeit to a lesser extent. However, this antagonist was unable to correct the impairment caused by alcohol abstinence in serotonin and neuropeptide Y. The endocannabinoid activity in the brain of alcohol-abstinent rats indicated that the behavioral and neurochemical improvements caused by rimonabant were not related to the attenuation of a possible increase in this activity generated by alcohol withdrawal. Conversely, the density of CB1 receptors was reduced in alcohol-abstinent animals (e.g. globus pallidus, substantia nigra), as were the levels of endocannabinoids and related N-acylethanolamines (e.g. amygdala, caudate-putamen). Thus, rimonabant possibly enhances an endogenous response generated by interrupting the regular use of alcohol. In summary, rimonabant might attenuate withdrawal symptoms associated with alcohol abstinence, an effect that was presumably due to the normalization of GABA and glutamate, and to a lesser extent, dopamine transmission in emotion- and motor-related areas.


Subject(s)
Anxiety/prevention & control , Anxiety/psychology , Brain Chemistry/drug effects , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Substance Withdrawal Syndrome/drug therapy , Substance Withdrawal Syndrome/psychology , Animals , Anxiety/etiology , Appetite/drug effects , Arachidonic Acids/pharmacology , Autoradiography , Benzoxazines/pharmacology , Cannabinoid Receptor Modulators/metabolism , Chromatography, High Pressure Liquid , Emotions/physiology , Endocannabinoids , Enkephalins/biosynthesis , Ethanolamines/pharmacology , Glycerides/pharmacology , In Situ Hybridization , Male , Morpholines/pharmacology , Motor Activity/drug effects , Naphthalenes/pharmacology , Neuropeptide Y/metabolism , Neurotransmitter Agents/metabolism , Piperidines/pharmacology , Polyunsaturated Alkamides/pharmacology , Protein Precursors/biosynthesis , Pyrazoles/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Wistar , Rimonabant , Stress, Psychological/psychology
6.
J Steroid Biochem Mol Biol ; 84(5): 543-53, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12767279

ABSTRACT

In earlier studies, we reported reduced human insulin receptor (hIR) mRNA levels, insulin binding and insulin responsiveness in U-937 human promonocytic cells treated with aldosterone. The mechanism for this inhibition could be diminished IR gene transcription, since aldosterone did not affect hIR mRNA stability. All the effects were mediated by a downregulation of the mineralocorticoid receptor (MR, NR3C2) expressed at both the RNA and protein levels, suggesting that MR could act as a transcription factor that binds to hormone response elements in the hIR gene promoter. Indeed, MR has been shown to bind glucocorticoid response elements (GREs) in target genes. Given that five GREs have been characterized in the hIR promoter, we decided to test whether these elements could mediate the aldosterone-elicited inhibition of hIR expression detected by us in U-937 cells. In the present report, we demonstrate that aldosterone inhibits the activity of the hIR wild-type promoter by 23%, and causes 23 and 31% reductions in the activity of progressive deletions of this promoter comprised of fragments up to -1473 and -876bp, respectively. This indicates that the -876 to -271bp region of the hIR promoter may be sufficient for this transcriptional inhibition by aldosterone. We also provide evidence for direct MR interaction with some of the GREs of this promoter region, specifically with the cGRE1 and cGRE3, presumably as MR-MR homodimers, and with pGRE as a MR-GR heterodimer. This heterodimer may play the most relevant role and participate in the cross-talk between mineralocorticoids, glucocorticoids and insulin signalling in U-937 cells.


Subject(s)
Aldosterone/pharmacology , Receptor, Insulin/antagonists & inhibitors , Transcription, Genetic/drug effects , Base Sequence , Consensus Sequence , Dexamethasone/pharmacology , Dimerization , Electrophoretic Mobility Shift Assay , Humans , Luciferases/genetics , Promoter Regions, Genetic/genetics , Receptor, Insulin/biosynthesis , Receptor, Insulin/genetics , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Response Elements/genetics , Transfection , U937 Cells
7.
J Steroid Biochem Mol Biol ; 84(2-3): 223-30, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12711007

ABSTRACT

The present study was designed to explore the possible presence and location of Vitamin D response elements (VDREs) in the human insulin receptor (hIR) gene promoter. To this end, the -1819 to -271 bp fragment of the hIR promoter (wild type promoter) and progressive 5' deletions of this promoter (up to -1473 and -876 bp) were linked to the luciferase pGL2-basic vector to construct the reported plasmids: phIR (-1819)-GL2, phIR(-1473)-GL2 and phIR(-876)-GL2, respectively. U-937 cells were transiently transfected with these plasmids, and then the cells were either untreated or treated for 24h with 10(-8) M 1,25-dihydroxyvitamin D(3) (1,25D(3)). Luciferase determinations revealed that, while the activity of the wild promoter was increased 1.6-fold by the hormone, the activities of progressive 5' deletions of this promoter were enhanced 1.7-, and 1.6-fold, respectively. Thus, the region extending from -876 to -271bp of the hIR promoter, appears to contain VDREs, and to be sufficient for induction by 1,25D(3). In order to identify these potential VDREs, we performed a computer search of candidate sequences by homology with a consensus VDRE sequence. This search yielded a sequence located between -761 and -732 bp (5'CGTCGGGCCTGTGGGGCGCCTCCGGGGGTC3'), which includes an overlapping AP-2 like sequence, as a good candidate. Electrophoretic mobility shift assays revealed that the Vitamin D receptor (VDR) specifically recognized this sequence, since a VDR-DNA complex was able to compete with the unlabeled probe and was cleared by the specific anti-VDR antibody 9A7. These data represent the first identification of a VDRE in the hIR gene promoter.


Subject(s)
Promoter Regions, Genetic , Receptor, Insulin/genetics , Vitamin D/metabolism , Cell Line , DNA/metabolism , Gene Deletion , Genetic Vectors , Humans , Luciferases/metabolism , Monocytes/metabolism , Plasmids/metabolism , Response Elements , Signal Transduction , Software , Time Factors , Transfection , U937 Cells
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