Peptide YY and vitamin E inhibit hormone-sensitive and -insensitive breast cancer cells.

We have shown that peptide YY, an endogenous gut hormone, and vitamin E succinate (VES) inhibit pancreatic cancer cell growth in vitro. We hypothesized that PYY and VES would inhibit breast cancer cell viability regardless of the hormone receptor status. Human breast ZR-75 ductal carcinoma (estrogen receptor negative) and MCF-7 adenocarcinoma (estrogen receptor positive) cells were cultured and exposed to VES (10 pg/ml), PYY (500 pmol), or both agents together. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability. At every time interval, PYY and VES significantly inhibited cell growth compared to control. The effects of PYY were similar in magnitude to those of VES. Combining the agents resulted in a significant additive inhibition of growth with the greatest effect seen at 72 h. We have shown that PYY and vitamin E inhibit in vitro growth of breast cancer cells with variable hormone receptor status. When used in combination, the agents have a significant increase in effect. Further studies are ongoing to define the mechanism of action of these agents and to translate the experiments to an in vivo model.

Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth.

BACKGROUND: Vitamin E succinate (VES) significantly inhibits cell growth in vitro in breast, prostate, and skin cancer cell lines. Our study demonstrated similar inhibitory effects on Mia PaCa-2 pancreatic cancer cells at the same concentration of VES (10 pg/ml). Peptide YY (PYY) also inhibits pancreatic cancer cell growth in vitro. We observed a significant additive effect on growth inhibition in Mia PaCa cells treated with both VES and PYY. METHODS: Human pancreatic ductal adenocarcinoma Mia PaCa-2 cells were cultured and treated once with either 10 pg/ml of VES or 500 pmols of PYY or with both agents together. The control group received an equivalent volume of solvents. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability. RESULTS: Pancreatic cancer cell growth was reduced in all groups treated with PYY and VES. Student's t test was used to analyze the data for each treatment group. At 72 h, both PYY and vitamin E significantly inhibited cell growth compared to control. Combining the agents resulted in a dramatic additive inhibition of growth. CONCLUSION: PYY and vitamin E both inhibit growth of pancreatic cancer cells in vitro with a significant increase in effect when used in combination.

Intestinal ischemia and the gut-liver axis: an in vitro model.

BACKGROUND: Sustained intestinal ischemic injury often leads to shock and multiorgan failure, mediated in part by a cytokine cascade. Animal models have also identified a central role of Kupffer cells in amplification of cytokines following intestinal ischemia. To better understand this gut-liver axis, we developed an in vitro model. MATERIALS AND METHODS: Kupffer cells were isolated from rat livers by arabinogalactan gradient ultracentrifugation and adherence purification. Cells were grown in RPMI medium in 5% CO(2). Rat intestinal epithelial cells, IEC-6, were cultured under normoxic or anoxic (90% N(2), 10% CO(2)) conditions for 2, 12, and 24 h. Kupffer cells were then grown in the conditioned medium of the IEC-6 cultures. After 24 h, the medium was replaced with fresh medium. This final Kupffer cell supernatant was tested for tumor necrosis factor alpha and interleukin-6 production by ELISA. Trypan blue exclusion was performed to assess cell viability. RESULTS: Intestinal and Kupffer cells remained viable during the experimental time. Production of both tumor necrosis factor alpha and interleukin-6 by Kupffer cells increased with increasing ischemia time of the intestinal cells. CONCLUSIONS: Consistent with animal studies of intestinal ischemia, this study found an increase in cytokine production by Kupffer cells following hypoxia of intestinal cells. This in vitro model offers a new tool to study the expression of cytokines, proteins, and messengers involved in the cascade of events that follow intestinal ischemia.

Renoprotective effects of the 21-aminosteroid U74389G in ischemia-reperfusion injury and cold storage preservation.

Free radical mediated lipid peroxidation (LPO) has been implicated in the pathogenesis of ischemic-reperfusion injury (IRI). To address the renoprotective effect(s) of LPO inhibition, the efficacy of the 21 aminosteroid U74389G was evaluated in three IRI models. In Model 1 51 unilateral nephrectomized rats that underwent 60 min of warm ischemia followed by a 72-hr reperfusion interval were treated with the test vehicle only, or 3, 6, or 12 mg/kg of U74389G intravenously, 5 min pre- or postischemia. In Model 2 Sprague-Dawley rats underwent sham operation (n=9), or 45 min of warm ischemia and 10 min of reperfusion with U74389G (6 mg/kg; n=10) or test vehicle only (n=10) administered intravenously over 10 min beginning 5 min prior to clamp release. After reperfusion, LPO was determined by assay of snap frozen tissue for thiobarbituric acid (TBA) concentrations (nmol/g tissue weight). In Model 3 domestic lean maid pigs (14-18 kg) underwent left nephrectomy with 30 min of warm ischemia, Collins C-4 flush, and 24 hr of cold storage preservation. Heterotopic autotransplantation and immediate contralateral nephrectomy was then performed in Group A-nonischemic controls (n=4), Group B-ischemic controls (n=5), and Group C-U74389G (6 mg/kg) administered preischemia and at autotransplantation (n=5). In Model 1 maximal renoprotection was demonstrated with the 6 mg/kg dose of U74389G administered after ischemia (ischemic control 72-hr serum creatinine (Cr) = 8.01+/-1.1 mg% vs. 3.32+/-0.96 mg%; ischemic control creatinine clearance = 0.069+/-0.03 ml/min vs. 0.206+/-0.04 ml/min; P<0.05). In Model 2 TBA levels were significantly lower in U74389G treated animals (88.5+/-10.0 vs. ischemic controls = 296.8+/-81.4; P=0.02). In Model 3 graft survivals were 100%, 0%, and 60% respectively. Peak Cr and BUN (mg%) were significantly greater in Group C vs. Group A, (Group A Cr = 8.59+/-0.63 vs. Group C = 12.8+/-1.01; Group A BUN = 64.1+/-2.73 vs. Group C = 104.9+/-12.21)--however, by day 10, thee were no significant differences in renal function: (Group A Cr = 2.15+/-0.3 vs. Group C = 2.10+/-0.06; Group A BUN = 27.0+/-6.0 vs. Group C = 31.1+/-6.4). These results support the beneficial effects of LPO inhibitors in models of ischemia-reperfusion, as well as preservation/transplantation, and suggest that this renoprotection correlates with decreased membrane lipid peroxidation.

Evaluation of the thromboxane A2 synthetase inhibitor OKY-046 in a warm ischemia-reperfusion rat model.

The pathophysiology of ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting prostanoid thromboxane A2 (TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective thromboxane synthetase inhibitor, OKY-046, in a unilateral nephrectomized, 60 min ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right nephrectomy only (group A), or right nephrectomy with 60 min of left renal ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma creatinine (CR); urea nitrogen (BUN); thromboxane B2 (TXB2) and 6-keto prostaglandin F(1alpha) (6 kPGF(2alpha)) levels; creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of OKY-046 administered after renal ischemia. (group B 72 hr Cr= 8.01 +/- 1.1 mg% vs. group E=3.99 +/- 1.5 mg%, and group B 72 hr BUN=241.3 +/- 32.8 mg% vs. group E=52.6 +/- 22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance (group B=0.069 ml/min vs. group E=0.194 ml/ min). The 24 hr TXB2 levels were significantly increased in group B (0 hr=754.1 +/- 219.4 pg/ml vs. 24 hr=2055.9 +/- 550.0 pg/ml), and pre- or posttreatment with OKY-046 abrogated this increase (group C 0 hr=517.1 +/- 80.9 pg/ml vs. 24 hr=384.7 +/- 251.5 pg/ml, and group E 0 hr=781.6 +/- 390.4 pg/ml vs. 24 hr=183.0 +/- 81.4 pg/ml). The 24 hr 6 kPGF(1alpha) levels decreased in all groups, whereas 72 hr 6 kPGF(1alpha) levels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of thromboxane A2 synthesis inhibition in the setting of ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory prostanoid synthesis.

Post-transplant hyperlipidemia: risk factors and response to dietary modification and gemfibrozil therapy.

A retrospective chart analysis of 200 consecutive, cyclosporine-treated, renal allograft recipients, transplanted between January 1988 and June 1992, was conducted to determine the incidence of and the etiologic variables for post-transplant hypercholesterolemia. In addition, the effectiveness of dietary intervention alone or in combination with gemfibrozil (600 mg b.i.d.), in post-transplant hypercholesterolemia was evaluated. Hypercholesterolemia (> or = 240 mg/dl on two separate determinations, while on maintenance immunosuppression) was present in 138 patients (Group A-69%). When compared to the remaining 62 patients without hypercholesterolemia (Group B-31%), there were no differences in mean age, body weight at transplantation, race, incidence of overt diabetes, systolic and diastolic blood pressure, or serial serum creatinine, albumin, and cyclosporine levels between these groups. Post-transplant hypercholesterolemia was significantly more prevalent in females, in recipients with higher baseline serum total cholesterol levels (mean +/- SEM, Group A = 229.0 +/- 5.0 vs. Group B = 192.0 +/- 6.1 mg/dl, p < 0.001), and in recipients with an elevated fasting blood glucose at 1 year post-transplant (Group A = 150.5 +/- 10.5 vs. Group B = 105.2 +/- 10.7 mg/dl, p < 0.05). In all patients with hypercholesterolemia, a hypocaloric low fat and low cholesterol (< 300 mg/day) diet was initiated at a mean of 0.59 +/- 0.06 years after transplantation with grading of dietary compliance at each follow-up visit (Grade 1, < 300 mg cholesterol; Grade 2, 300-500 mg cholesterol; Grade 3, > 500 mg cholesterol intake in 24 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Sentinel health events as indicators of unmet needs.

It is vitally important to be able to assess the impact of the health care system on the populations it serves. This paper explores whether sentinel health events--negative health states, such as death, disability, and disease, that might have been avoided given current medical and public health knowledge and technology--can be used as sociomedical indicators to assess levels of unmet needs and to evaluate health system performance. Using hospital discharge data, the occurrence of sentinel health events in New York State and differences among population subgroups are examined. Among hospitalized residents of New York State in 1983, more than 17,000 deaths occurred that were possibly avoidable. More than 336,000 instances of disease were found that were potentially preventable. Significantly higher rates and ratios for many sentinel events were found among blacks, Medicaid recipients, and users of public hospitals than were found for comparison groups. The sentinel events approach proved to be useful and practical. However, refinements and adaptations of the sentinel events method are needed, including the development of one or more smaller sets of indicators--tracer sentinel events--that can be used to profile aspects of health status and the health system.

Measuring avoidable deaths and diseases in New York State.

The measurement of sentinel health events--avoidable deaths and diseases--is a practical and valuable method for assessing the state of the community's health and the performance of the health system in meeting the needs of the population. A comprehensive framework for identification of sentinel health events has been defined by the Working Group on Preventable and Manageable Diseases. The Working Group developed lists that include more than 120 medical conditions for which death or disease is deemed to be potentially avoidable through primary prevention activities or timely and appropriate treatment. Hospital discharge abstract data offer a unique perspective for examining these potentially avoidable negative health outcomes. Such data, available in New York State through the Statewide Planning and Research Cooperative System (SPARCS), are a source of detailed and accessible information on a wide range of morbidity-producing conditions and associated deaths. Among the findings of this sentinel health events study, based on an analysis of SPARCS data, are the following: Among hospitalized residents of New York State in 1983, more than 19,000 deaths occurred that were potentially avoidable. More than one-third of these deaths occurred among persons under age 65. More than 336,000 instances of disease were found that were potentially preventable, amounting to 123 disease occurrences per 1,000 discharges. In the category of sentinel events where each event may be avoidable, only three conditions alone were associated with 75 percent of the deaths and 60 percent of the disease occurrences--malignant neoplasm of the trachea, bronchus, and lung; emphysema or chronic obstructive lung disease(s); and malignant neoplasm of the bladder. In the category of events where some proportion of events may be avoidable, one diagnosis--vascular complications associated with hypertensive disease(s)--was linked with 45 percent of the deaths. Significantly higher rates and ratios for many sentinel events were found among blacks, Medicaid recipients, and users of public hospitals than were found for comparison groups. For example, among patients hospitalized for colon and related neoplasms, black patients were more than twice as likely to die than white patients.(ABSTRACT TRUNCATED AT 400 WORDS)