Atherosclerosis of brachiocephalic arteries and arterial stiffness in patients with breast cancer.

Cardiovascular toxicity is one of the important problems of clinical oncology. Atherosclerosis progression was demonstrated in patients with cancer and chemotherapy.Te aim - to evaluate the vascular wall characteristics and to determine the predictors of AS of brachiocephalic arteries progression during anticancer therapy in patients with breast cancer. METHODS: Te study involved 43 patients with newly diagnosed breast cancer (BC) (II-III stage) with overexpression of HER2; median age 50 (40;57) years. All patients underwent neoadjuvant drug therapy with antracyclines, taxanes and trastuzumab followed by surgery, radiation and hormone therapy according to the indications. Before anticancer therapy the general clinical examination was conducted and lipid profle, plasma lipoprotein (a) [Lp(a)] level, titres of autoantibodies IgM and IgG to lipoproteins and their oxidized derivatives were estimated. Te vascular wall stiffness (pulse wave velocity on the carotid-femoral (PWVcf) and shoulder-ankle (PWVsa) segments, the central pressure, carotid intima-media thickness (CIMT) and the degree of stenosis of the brachiocephalic arteries) were determined at baseline and at each stage of anticancer therapy. Te atherosclerosis progression was determined if the new stenosis (≥15%) or increase of preexisting stenosis (≥5%) were revealed; CIMT increase ≥ 0.1 mm. Te parameters of cellular immunity (peripheral blood lymphocyte phenotyping via direct immunofluorescence and flow cytometry), lipid spectrum parameters, serum concentration of Lp (a), autoantibodies IgM and IgG against lipoproteins and their oxidized derivatives, as well as PWVсf and PWVsa were assessed in 17 BC patients before the onset of neoadjuvant therapy and in 20 healthy women. RESULTS: BC patients and healthy women were comparable in traditional cardiovascular risk factors but differed in PWVsa and PWVcf levels (p<0.05). In BC patients the activation of T-cell immunity with the stimulation of both subpopulations with pro-inflammatory and regulatory properties was observed (p<0.05). Te direct correlations between the content of activated T-lymphocytes (T-act), T-helpers (T) 1 and PWVsa (p<0.05), as well as T-act, T1 and T2 and PWVcf (p<0.05) were revealed in the general group. Te decrease of systolic blood pressure (SBP), central SBP (SBPc), central diastolic blood pressure (DBPc), PWVcf and PWVsa levels accompanied with a temporary heart rate increase were observed during anticancer therapy; SBP, SBPc, PWVcf levels restored by the end of the follow-up period. Te CIMT increase was detected in 22 (51%), and the atherosclerosis progression in 26 (60%) BC patients during anticancer therapy. Lp (a) level above 12.8 mg/dl was associated with CIMT increase (p<0.05). Age > 48 years and radiation therapy were risk factors for CIMT increase and atherosclerosis progression (p<0.05), respectively. CONCLUSIONS: Te vascular stiffness is increased in BC patients, which is associated with the activation of effector subpopulations of T-lymphocytes and the elevation of circulating level of both pro-atherogenic and anti-atherogenic T-cells. Te level of Lp (a) above 12.8 mg/dl is associated with atherosclerosis progression, which requires further research. Age and radiation therapy are the risk factors for atherosclerosis progression during anticancer therapy.

Cysteine-Containing Peptides Stimulate Monocyte Migration through NADPH-Oxidase Activation.

We analyzed migration of monocytes under the effect of apocinin (NADPH inhibitor) and PD98059 (blocker of extracellular MEK/ERK kinase involved in Nox4 oxidase-mediated migration of monocytes). Migration of monocytes stimulated by cysteine-containing peptides (fragments of chemokines with free thiol group MCP-1 and fractalkine) was completely inhibited by apocinin and MEK/ERK blocker. It is assumed that the stimulating effect of cysteine-containing peptides on monocyte migration is mediated by the NADPH-oxidase system, in particular, Nox4.

Ingramon, a Peptide Inhibitor of MCP-1 Chemokine, Reduces Migration of Blood Monocytes Stimulated by Glioma-Conditioned Medium.

Malignant gliomas are most common and fatal primary brain tumors. In addition to neoplastic cells, the tumor tissue contains microglial cells and monocyte-derived macrophages. It is an established fact that monocyte recruiting promotes the tumor growth and dissemination. Monocyte chemotactic protein-1 (MCP-1) is the major attractant for monocytes. We have previously synthesized an MCP-1 antagonist ingramon, a synthetic peptide fragment (65-76) of this chemokine. In the present study, we demonstrated that glioma-conditioned medium contains MCP-1 and stimulates migration of blood monocytes. Ingramon inhibited the effect of glioma-conditioned medium on monocyte migration.

[Cys-containing peptides cause migration of monocytes].

Automated Fmoc solid-phase technique was used to synthesize Cys-containing linear peptide fragments of monocyte chemoattractant protein-1 and chemokine domain of fractalkine along with their analogues with Cys residue being either modified or replaced with Ser. Chimeric symmetric and asymmetric disulfides were also prepared from the former linear precursors. A SAR study on a set of the newly synthesized peptides revealed that capacity to stimulate migration of monocytes and to influence cell motility in vitro, in general, critically depends on the presence of Cys free thiol group in the molecule. Notably, all analogs lacking this feature, including chimeric disulfides, demonstrated lack of effect on monocyte migration.