Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study.

BACKGROUND: The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. METHODS AND FINDINGS: Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. CONCLUSIONS: This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

Effects of tomato and soy on serum adipokine concentrations in postmenopausal women at increased breast cancer risk: a cross-over dietary intervention trial.

CONTEXT: Breast cancer risk among postmenopausal women increases as body mass index increases. Practical preventive methods to reduce risk of breast cancer are lacking. Few studies have investigated the effects of carotenoids and isoflavones on circulating adipokines in postmenopausal women. OBJECTIVE: The aim was to examine the effects of lycopene- and isoflavone-rich diets on serum adipokines. DESIGN: This was a 26-week, two-arm, longitudinal crossover trial. SETTING: Participants were recruited from clinics at The Ohio State University Comprehensive Cancer Center. PARTICIPANTS: Seventy postmenopausal women at increased breast cancer risk participated in the study. The mean age and body mass index of participants was 57.2 years and 30.0 kg/m(2), respectively; the study was comprised of 81.4% whites. INTERVENTIONS: The interventions included 10 weeks of consumption of a tomato-based diet (≥25 mg lycopene daily) and 10 weeks of consumption of a soy-based diet (≥40 g of soy protein daily), with a 2-week washout in between. MAIN OUTCOME MEASURES: Changes in serum adiponectin, leptin, and the adiponectin to leptin ratio were examined for each intervention through linear mixed models, with ratio estimates corresponding to postintervention adipokine concentrations relative to preintervention concentrations. RESULTS: After the tomato intervention, among all women, adiponectin concentration increased (ratio 1.09, 95% confidence interval (CI) 1.00-1.18), with a stronger effect observed among nonobese women (ratio 1.13, 95% CI 1.02-1.25). After the soy intervention, adiponectin decreased overall (ratio 0.91, 95% CI 0.84-0.97), with a larger reduction observed among nonobese women (ratio 0.89, 95% CI 0.81-0.98). Overall, no significant changes in leptin or the adiponectin to leptin ratio were observed after either intervention. CONCLUSIONS: Increasing dietary consumption of tomato-based foods may beneficially increase serum adiponectin concentrations among postmenopausal women at increased breast cancer risk, especially those who are not obese. Additional studies are essential to confirm these effects and to elucidate the specific mechanisms that may make phytonutrients found in tomatoes practical as breast cancer chemopreventive agents.

Randomized controlled trial of docosahexaenoic acid supplementation in midwestern U.S. human milk donors.

BACKGROUND: Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid important for neonatal neurodevelopment and immune homeostasis. Preterm infants fed donor milk from a Midwestern source receive only 20% of the intrauterine accretion of DHA. We tested the hypothesis that DHA supplementation of donor mothers would provide preterm infants with DHA intake equivalent to fetal accretion. SUBJECTS AND METHODS: After Institutional Review Board approval and informed consent, human milk donors to the Mother's Milk Bank of Ohio were randomized to receive 1 g of DHA (Martek(®) [now DSM Nutritional Lipids, Columbia, MD]) or placebo soy oil. Dietary intake data were collected and analyzed by a registered dietitian. Fatty acids were measured by gas chromatography/flame ionization detection. Statistical analysis used linear mixed models. RESULTS: Twenty-one mothers were randomly assigned to either the DHA group (n=10) or the placebo group (n=11). Donor age was a median of 31 years in both groups with a mean lactational stage of 19 weeks. Dietary intake of DHA at baseline in both groups was a median of 23 mg/day (range, 0-194 mg), significantly (p<0.0001) less than the minimum recommended intake of 200 mg/day. The DHA content of milk increased in the DHA-supplemented group (p<0.05). CONCLUSIONS: The women enrolled in this study had low dietary DHA intake. Supplementation with preformed DHA at 1 g/day resulted in increased DHA concentrations in the donor milk with no adverse outcomes. Infants fed donor milk from supplemented women receive dietary DHA levels that closely mimic normal intrauterine accretion during the third trimester.

Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice.

DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1ß, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.