trp-lys-tyr-met-val-met and Neoplasms

Bacterial infections are major life-threatening complications in patients receiving cytotoxic drugs. These infections generally occur during periods of neutropenia. It has been suggested that the incidence of neutropenia correlates with the incidence of infections. A synthetic hexapeptide, WKYMVm, which stimulates phosphoinositide hydrolysis in leukocytes, has been shown to activate microbicidal activities of human polymorphonuclear neutrophils. In this study, we evaluate whether WKYMVm stimulates bactericidal activity in neutrophils obtained from patients who received chemotherapy for solid tumors when they were neutropenic. Eight patients and 11 healthy controls were recruited for the study. Patient neutrophils, on day 0 and at 2 weeks after chemotherapy, were collected. Expression of the WKYMVm peptide receptor, on leukocytes, was analyzed by fluorescein-activated cell sorting. Neutrophil bactericidal assays were performed using both reactive oxygen species generation and intracellular killing. Expression of the WKYMVm peptide receptor on leukocytes showed no difference in the treated patients compared to healthy controls. WKYMVm increased bactericidal activities, in a dose-dependent fashion, of control neutrophils compared to treated patient neutrophils obtained on day 0. WKYMVm markedly stimulated bactericidal activity of treated patient neutrophils obtained at 2 weeks after chemotherapy compared to treated patient neutrophils obtained on day 0. WKYMVm augmented neutrophil bactericidal activity was noted at low concentration but was suppressed at higher concentrations of 5-fluorouracil. WKYMVm augmented neutrophil bactericidal activity was not suppressed by cisplatin. WKYMVm has the potential for increasing neutrophil bactericidal activity in chemotherapy-treated cancer patients.

Topics: Adult; Aged; Bacterial Infections; Blood Bactericidal Activity; Cells, Cultured; Cisplatin; Dose-Response Relationship, Drug; Drug Antagonism; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Neutrophil Activation; Neutrophils; Oligopeptides; Receptors, Cell Surface

Dendritic cells (DCs) play a key role in activating the immune response against invading pathogens as well as dying cells or tumors. Although the immune response can be initiated by the phagocytic activity by DCs, the molecular mechanism involved in this process has not been fully investigated. Trp-Lys-Tyr-Met-Val-Met-NH(2) (WKYMVM) stimulates the activation of phospholipase D (PLD) via Ca(2+) increase and protein kinase C activation in mouse DC cell line, DC2.4. WKYMVM stimulates the phagocytic activity, which is inhibited in the presence of N-butanol but not t-butanol in DC2.4 cells. Furthermore, the addition of phosphatidic acid, an enzymatic product of PLD activity, enhanced the phagocytic activity in DC2.4 cells. Since at least two of formyl peptide receptor (FPR) family (FPR1 and FPR2) are expressed in DC2.4 as well as in mouse bone marrow-derived dendritic cells, this study suggests that the activation of FPR family by WKYMVM stimulates the PLD activity resulting in phagocytic activity in DC2.4 cells.

Topics: 1-Butanol; Animals; Bone Marrow Cells; Calcium Signaling; Cell Death; Cell Line; Communicable Diseases; Dendritic Cells; Mice; Neoplasms; Oligopeptides; Phagocytosis; Phosphatidic Acids; Phospholipase D; Receptors, Formyl Peptide; tert-Butyl Alcohol