64 results match your criteria: "McGill University Health Center - Royal Victoria Hospital[Affiliation]"

This debate is designed to review the usefulness of the cholesterol mass within high-density lipoproteins (HDL-C) to predict the risk of atherosclerotic cardiovascular disease (ASCVD). PRO: There is much current confusion regarding the role of high density lipoproteins (HDLs) in atherosclerotic cardiovascular disease (ASCVD). While it is an established fact that the concentration of HDL cholesterol is a robust, independent, inverse predictor of the risk of having an ASCVD event, recent studies have questioned whether HDLs actually protect against ASCVD.

View Article and Find Full Text PDF

The incidence of metastatic melanoma has been increasing dramatically over the last decades. Yet, there have been many new innovative therapies, such as targeted therapies and checkpoint inhibitors, which have made progress in survival for these patients. The oncology pharmacist is part of the healthcare team and can help in optimizing these newer therapies.

View Article and Find Full Text PDF

Background: Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported.

View Article and Find Full Text PDF

Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone-related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA).

View Article and Find Full Text PDF

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention.

View Article and Find Full Text PDF

Cancer cells are characterized by a complex network of interrelated and compensatory signaling driven by multiple kinases that reduce their sensitivity to targeted therapy. Therefore, strategies directed at inhibiting two or more kinases are required to robustly block the growth of refractory tumour cells. Here we report on a novel strategy to promote sustained inhibition of two oncogenic kinases (Kin-1 and Kin-2) by designing a molecule K1-K2, termed "combi-molecule", to induce a tandem blockade of Kin-1 and Kin-2, as an intact structure and to be further hydrolyzed to two inhibitors K1 and K2 directed at Kin-1 and Kin-2, respectively.

View Article and Find Full Text PDF

To potentiate the quinazoline-based inhibitor of the epidermal growth factor receptor (EGFR), a chloroethyl alkylating moiety was appended to its 6-position. This led to molecules with extremely strong EGFR inhibitory potency and anomalously strong DNA-damaging potential. To assess the role of the chloroethyl group on potency, we designed a molecule in which it is shifted to the 7-position where it would be less reactive and away from the cys773 of the EGFR ATP site.

View Article and Find Full Text PDF

Purpose Of Review: To examine the current and future therapeutic option of HDL-based therapies.

Recent Findings: The inverse association between plasma level of high-density lipoprotein cholesterol (HDL-C) is strong and coherent across the population studied. In-vitro and in-vivo studies show the strong biological plausibility for HDL as a therapeutic target.

View Article and Find Full Text PDF

Background: Impairment of acid sphingomyelinase (SMase) results in accumulation of sphingomyelin (SM) and cholesterol in late endosomes, the hallmarks of a lysosomal storage disease.

Objective: We describe cellular lipid metabolism in fibroblasts from two patients with novel compound heterozygote mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene manifesting as Niemann-Pick disease type B (NPB) and demonstrate mechanisms to overcome the storage defect.

Methods: Using biochemical assays and confocal microscopy, we provide evidence that accumulated lysosomal SM and cholesterol can be released by different treatments.

View Article and Find Full Text PDF

Biological effects of AL622, a molecule rationally designed to release an EGFR and a c-Src kinase inhibitor.

Chem Biol Drug Des

December 2012

Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West Rm M-719, Montreal, Quebec, H3A 1A1 Canada.

In breast cancer cells expressing c-Src and EGFR, a control of one of the two oncogenes over proliferation and invasion is observed, whereas in others, the synergistic interaction between them is required for tumor progression. With the purpose of developing molecules with the highest probability for blocking the adverse effects of these two oncogenes, we designed AL622, which contains a quinazoline head targeted to EGFR and a linker that bridges it to the PP2-like structure for targeting c-Src. In case the entire molecule would not be capable of blocking c-Src, we designed AL622 to hydrolyze to an intact c-Src-targeting PP2 molecule.

View Article and Find Full Text PDF

ZRBA1 is a quinazoline-based molecule termed 'combi-molecule' designed to block the epidermal growth factor receptor (EGFR) and further degrade to FD105, an EGFR inhibitor plus a DNA-alkylating agent. To augment the potency of ZRBA1, we designed JDE52, a bistriazene that, following degradation, was 'programmed' to yield higher concentrations of the free inhibitor FD105 and a more cytotoxic bifunctional DNA-damaging species. The results indicated that JDE52 was capable of inducing significant blockade of EGFR phosphorylation, DNA strand breaks and interstrand cross-links in human cells.

View Article and Find Full Text PDF

Purpose: At the preclinical stage, mitozolomide (MTZ) showed exciting preclinical activity but failed later in clinical trial due to toxic side effects. We surmised that by targeting MTZ to epidermal growth factor receptor (EGFR), we may not only alter its toxicity profile, but also enhance its potency in EGFR-overexpressing tumors. To test this hypothesis, we designed JDF12, studied its mechanism of action in human prostate cancer (PCa) cells and determined its potency in vivo.

View Article and Find Full Text PDF

The liver is a common site for cancer metastases in which the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the proapoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a proinflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacities of poorly metastatic cells in the liver.

View Article and Find Full Text PDF

Capecitabine (Xeloda) is a prodrug of 5-FU used in the clinical management of advanced breast cancer. It is metabolized first in the liver by carboxylesterases to generate 5'-deoxy-5-flurocytidine ribose (5'-DFCR), which is subsequently converted to 5'-deoxy-5-fluorouridine ribose (5'-DFUR) by cytidine deaminase in tumour and normal tissues. The conversion of 5'-DFUR to the cytotoxic 5-FU, occurs primarily in the tumour and is catalyzed by thymidine phosphorylase (TP).

View Article and Find Full Text PDF

Recent studies have identified an ABCA1-dependent, phosphatidylcholine-rich microdomain, called the "high-capacity binding site" (HCBS), that binds apoA-I and plays a pivotal role in apoA-I lipidation. Here, using sucrose gradient fractionation, we obtained evidence that both ABCA1 and [¹²⁵I]apoA-I associated with the HCBS were found localized to nonraft microdomains. Interestingly, phosphatidylcholine (PtdCho) was selectively removed from nonraft domains by apoA-I, whereas sphingomyelin and cholesterol were desorbed from both detergent-resistant membranes and nonraft domains.

View Article and Find Full Text PDF

ZR2003 is a type II of combi-molecule designed to target DNA and the epidermal growth factor receptor (EGFR) without requirement for hydrolysis. In human tumour cell lines cultured as monolayers, it showed 6.5-35 fold greater activity than Iressa.

View Article and Find Full Text PDF

The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27(IGF-IR) murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo.

View Article and Find Full Text PDF

In vitro and in vivo biodistribution of ZRS1, a stabilized type I N-acetoxymethyl carbamate-containing combi-molecule.

Drug Metab Lett

April 2011

Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West Room M-7.19, Montreal, Quebec, H3A 1A1 Canada.

Combi-molecules are agents designed to block receptors on their own and to further degrade to bioactive agents. Here we studied the fate of a novel combi-molecule of triazene class termed "ZRS1" in biological medium using multilayer aggregates and mouse tumour models. ZRS1 is a second generation derivative of RB107, a prodrug designed to release an EGFR inhibitor FD105 plus a methyl diazonium species.

View Article and Find Full Text PDF

Synthesis and studies on three-compartment flavone-containing combi-molecules designed to target EGFR, DNA, and MEK.

Chem Biol Drug Des

May 2011

Cancer Drug Research Laboratory, Department of Medicine, Division of Medical Oncology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West Rm M-719, Montreal, Quebec H3A 1A1, Canada.

In order to induce a tandem targeting of EGFR, DNA, and MEK, we built complex combi-molecules containing an EGFR targeting quinazoline and an aminoethyltriazene moiety linking the entire molecule to PD98059. Two complex molecules were synthesized: one with a short aminoethyl spacer, AL232, and the other AL414 with a longer aminoethylaminoethyl spacer. AL414 was a more potent inhibitor of EGFR tyrosine kinase than AL232.

View Article and Find Full Text PDF

MGMT is a molecular determinant for potency of the DNA-EGFR-combi-molecule ZRS1.

Mol Cancer Res

March 2011

Cancer Drug Research Laboratory, Department of Medicine, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada.

To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazene-based DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT).

View Article and Find Full Text PDF

RB24 (NSC 741279), a 3-methyltriazene termed "combi-molecule" designed to possess mixed epidermal growth factor receptor (EGFR) targeting and DNA methylating properties showed over a 100-fold greater antiproliferative activity than Temodal(®) (TEM), a 4-fold greater potency than gefitinib and a 5-fold stronger activity than an equi-effective combination of gefitinib+TEM against the O(6)-alkylguanine transferase (AGT)-proficient DU145 cell line that co-expresses EGFR. Investigation of the mechanisms underlying the unique potency of RB24 revealed that cell exposure to TEM was accompanied by activation of p38MAPK and concomitant elevation of the levels of X-ray repair cross-complementing group 1 (XRCC1) protein. Levels of phospho-p38MAPK and XRCC1 were increased by 2-fold in EGF-stimulated cells.

View Article and Find Full Text PDF

The frailty syndrome is associated with inflammation, hypercortisolemia, and cardiovascular diseases, all of which are linked with insulin resistance. But whether frailty is characterized by insulin resistance is unclear, especially in the postprandial state. The prevalence of underweight with frailty is high.

View Article and Find Full Text PDF

Objectives: The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol (HDL-C) levels in vitro and in vivo.

Background: Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease.

Methods: HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production.

View Article and Find Full Text PDF

Previous strategies for stabilizing combi-triazenes were based on masking the 1,2,3-triazene chain with a 3-acetoxymethylene group. The half-lives of the latter molecules were only ca 5 min longer than those of their parent 1,2,3-triazenes. The novel combi-molecules described herein contain a hydrolysable carbamate group that modulates their kinetics of degradation.

View Article and Find Full Text PDF