Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20–30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/− piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0–24h decreased with 7.7% (95%CI: −15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: −21.9 to −1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0–24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients

Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing

Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPa checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPa interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor ciclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m−2 combined with CsA 10 mg kg−1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m−2 week−1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer

Neutrophils kill antibody-opsonized cancer cells by trogoptosis

Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPa checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPa interactions

Activation of high endothelial venules in peripheral lymph nodes.The involvement of interferon-gamma

The introduction of Freund's complete adjuvant into footpads of mice leads to functional changes of the high endothelial venules (HEV) in the draining lymph nodes. Using an in vitro adhesion assay, increased binding of monocytes and dendritic cells could be seen. These effects are also seen after injection of high doses of INF-gamma. No changes in the expression of vascular addressins, VCAM-1, E selection or ICAM-1 could be observed but the binding of monocytes could be blocked with an antibody against Mac-1. Depletion studies have made it clear that macrophages in the lymph node are not directly involved in the activation of the HEV. The induction of additional adhesion mechanisms on HEV could be an efficient way to recruit inflammatory cells into the lymph node, thereby regulating the local immune response

Activation of high endothelial venules in peripheral lymph nodes.The involvement of interferon-gamma

The introduction of Freund's complete adjuvant into footpads of mice leads to functional changes of the high endothelial venules (HEV) in the draining lymph nodes. Using an in vitro adhesion assay, increased binding of monocytes and dendritic cells could be seen. These effects are also seen after injection of high doses of INF-gamma. No changes in the expression of vascular addressins, VCAM-1, E selection or ICAM-1 could be observed but the binding of monocytes could be blocked with an antibody against Mac-1. Depletion studies have made it clear that macrophages in the lymph node are not directly involved in the activation of the HEV. The induction of additional adhesion mechanisms on HEV could be an efficient way to recruit inflammatory cells into the lymph node, thereby regulating the local immune response

Electron microscopic study of the localization of ferric iron in chorionic epithelium of the sheep placenta

The ferrocyanide method has been used to study, at the ultrastructural level, the maternal-fetal iron transfer in the chorionic epithelium of the haemophagous regions of the sheep placenta during the third trimester of gestation (at the 126th and the 145th day of gestation). No significant differences could be found in the distribution pattern of the ferrocyanide precipitate product within the chorionic epithelium in both stages of gestation. The presence of ferrocyanide reaction product in lysosomal structures, involved in the breakdown of maternal erythrocytes ingested by chorionic epithelial cells, confirmed that trivalent iron is liberated from digested haemoglobin. Ferric iron was also detected in the epithelial cytoplasmic matrix especially in the vicinity of erythrolysosomal structures, between the lateral surfaces of neighbouring epithelial cells, along the complex of interdigitating folds and the basal plasma membrane. Only on one occasion was the presence of ferric iron observed in the basal lamina, between the junctions of the endothelial cells and in their cytoplasmic matrix

Value of caregiver ratings in evaluating the quality of life of patients with cancer

PURPOSE: To evaluate the usefulness of caregiver ratings of cancer patients' quality of life (QL), we examined the following: (1) the comparability of responses to a brief standardized QL questionnaire provided by patients, physicians, and informal caregivers; and (2) the relative validity of these ratings. METHODS: The study sample included cancer patients receiving chemotherapy, their treating physicians, and significant others involved closely in the (informal) care of the patients. During an early phase of treatment and 3 months later, patients and caregivers completed independently the COOP/WONCA charts, covering seven QL domains. At baseline, all sources of information were available for 295 of 320 participating patients (92%). Complete follow-up data were obtained for 189 patient-caregiver triads. RESULTS: Comparison of mean scores on the COOP/WONCA charts revealed close agreement between patient and caregiver ratings. At the individual patient level, exact or global agreement was observed in the majority of cases (73% to 91%). Corrected for chance agreement, moderate intraclass correlations (ICC) were noted (0.32 to 0.72). Patient, physician, and informal caregiver COOP/WONCA scores were all responsive to changes over time in specific QL domains, but differed in their relative performance. Relative to the patients, the physicians were more efficient in detecting changes over time in physical fitness and overall health, but less so in relation to social function and pain. CONCLUSION: For studies among patient populations at risk of deteriorating self-report capabilities, physicians and informal caregivers can be useful as alternative or complementary sources of information on cancer patients' Q