Biomedical subjects

James A Bennett

Publications and source records attributed to James A Bennett.

9 recordsLinked to original sources

PubMed2006

Use of resveratrol to improve the effectiveness of cisplatin and doxorubicin: study in human gynecologic cancer cell lines and in rodent heart.

OBJECTIVE: The purpose of this study was to investigate whether resveratrol adds to the growth inhibitory effects of cisplatin and doxorubicin on ovarian and uterine cancer cells and to evaluate whether resveratrol diminishes the cardiac toxicity of doxorubicin in rodent heart. STUDY DESIGN: Human ovarian (OVCAR-3) and uterine (Ishikawa) cancer cells in culture were treated with cisplatin and doxorubicin, respectively, with and without resveratrol; and cell growth and viability were evaluated. Neonatal rat ventricular myocytes received doxorubicin in the presence and absence of resveratrol, and cell viability was evaluated. Mice received doxorubicin +/- resveratrol, and electrocardiograms were evaluated. Data were analyzed with analysis of variance and Scheffe's test. RESULTS: Resveratrol combined with cisplatin or with doxorubicin demonstrated an additive growth-inhibitory anticancer effect with a left shift of the cisplatin and doxorubicin dose/response curves. Resveratrol increased the viability of neonatal rat ventricular myocytes that were treated with doxorubicin and reduced doxorubicin-induced bradycardia and QTc interval prolongation in mice. CONCLUSION: Resveratrol adds to the growth inhibitory/anticancer activity of cisplatin and doxorubicin in vitro and protects against doxorubicin-induced cardiac toxicity both in vitro and in mice.

Animals↗

PubMed2006

AFPep: an anti-breast cancer peptide that is orally active.

BACKGROUND: We have synthesized a cyclic nonapeptide (AFPep) that is effective, after being administered by parenteral routes, for the treatment or the prevention of breast cancer. To test the hypothesis that AFPep remains safe and efficacious after oral administration, three different whole-animal bioassays were utilized, and the mechanism by which AFPep functions was investigated. METHODS: Using a human breast cancer xenograft model in mice for therapeutic activity, a carcinogen-induced breast cancer model in rats for prevention efficacy, and a mouse uterus growth inhibition model of anti-estrogenic activity, AFPep was administered by oral gavage (p.o.) and its effects compared to those following intraperitoneal (i.p.) and subcutaneous (s.c.) administration. Toxicity studies evaluated body weights and organ weights in mice and rats receiving AFPep. Preliminary mechanistic studies were carried out in T47D human breast cancer cells growing in culture and evaluated the effect of AFPep on estrogen-stimulated cell growth, phosphorylation of the estrogen receptor (ER), and on level of ER-related kinases. RESULTS: Orally administered AFPep stopped the growth of human tumor xenografts in mice, decreased the incidence and multiplicity of breast cancers in carcinogen-exposed rats, and inhibited the estrogen-stimulated growth of mouse uteri. In each of these systems, orally administered AFPep produced an effect similar to that obtained for AFPep administered by either i.p or s.c. routes. In rodents, no evidence of toxicity was seen for the peptide, even at very high doses. In culture, AFPep inhibited the estrogen-stimulated growth, but not the basal growth, of T47D cells, and it inhibited the estrogen-stimulated phosphorylation of Serine 118 in the ER of these cells, which was not explainable by early changes in ER-related kinases. CONCLUSIONS: Chronic oral administration of AFPep appears to be safe and effective for the treatment or prevention of breast cancer in animal models.

Administration, Oral↗

PubMed2005

Prevention of N-methyl-N-nitrosourea-induced breast cancer by alpha-fetoprotein (AFP)-derived peptide, a peptide derived from the active site of AFP.

PURPOSE: alpha-Fetoprotein (AFP) is a protein of pregnancy associated with a decrease in lifetime risk of breast cancer in parous women. A synthetic, cyclic nonapeptide has been developed that mimics the antioncogenic active site of AFP. To test the hypothesis that the AFP-derived peptide (AFPep) can prevent breast cancer, the N-methyl-N-nitrosourea-induced breast cancer model was used in rats. EXPERIMENTAL DESIGN: AFPep was given daily by injection beginning 10 days after N-methyl-N-nitrosourea treatment and continued for 23 days (a time designed to mimic pregnancy) or for other times to assess efficacy as a function of drug duration. Tumor incidence, multiplicity, and latency were noted as end points. At necropsy, pathology analysis of tumors and major organs were obtained. RESULTS: AFPep prevented cancer in a dose-dependent fashion. Significantly longer mean tumor-free days (P < 0.02), lower tumor incidence (P = 0.004), and lower tumor multiplicity were observed for AFPep-treated groups. No evidence of host toxicity as measured by body weight, cage activity, fur texture, and organ weights (liver, uterus, heart, kidney, and spleen) were found in animals treated with AFPep. Mechanistic studies using transplantable human breast cancer xenografts showed that the peptide interfered with estrogen-dependent breast cancer growth inhibited the phosphorylation of the estrogen receptor and activated phosphorylation of p53. CONCLUSIONS: AFPep is a well-tolerated, mechanistically novel, chemopreventive agent in models of breast cancer and warrants further development for the prevention and treatment of this disease in humans.

Alkylating Agents↗

PubMed2005

Rhodium catalysed hydroformylation of alkenes using highly fluorophilic phosphines.

Highly fluorophilic phosphines incorporating at least one aromatic ring containing two directly attached perfluoroalkyl groups have been synthesised, their partition coefficients (organic phase : fluorous phase) measured and their electronic properties probed using (1)J(PtP) data for their trans-[PtCl(2)L(2)] complexes. These phosphines have been used as modifying ligands for the rhodium catalysed hydroformylation of 1-octene in perfluorocarbon solvents. Catalyst activity, regioselectivity and the levels of rhodium leaching to the product phase vary with the substitution patterns of the modifying ligands that do not correlate with the electronic properties or partition coefficients of these ligands, but can be interpreted in terms of differences in the resting states of the catalysts.

Journal Article↗

PubMed2003

Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis.

PURPOSE: Elevated manganese superoxide dismutase (Sod2) levels have been reported to be associated with an increased frequency of tumor invasion and metastasis in certain cancers, and the aim of this study is to examine the molecular mechanisms by which this occurs. EXPERIMENTAL DESIGN: Sod2 and catalase overexpressing HT-1080 fibrosarcoma cell lines were used to evaluate the H(2)O(2)-dependent regulation of matrix metalloproteinase (MMP)-1 promoter activity, mitogen-activated protein (MAP) kinase signaling, DNA-binding activity, and MMP mRNA levels. The invasive and metastatic potential of Sod2 overexpressing cells was characterized using subrenal capsular implantation or tail vein injection of tumor cells into nude mice, respectively. RESULTS: Our data reveal that Sod2 overexpression increases the DNA-binding activity of transcription factors critical for MMP expression but also enhances MMP-1 promoter activity via the Ras//MAP/extracellular signal-regulated kinase (MEK) signaling cascade. A single nucleotide polymorphism that creates an Ets site at position -1607 bp confers Sod2-dependent MMP-1 promoter activity. Sod2 overexpression also increases the mRNA levels of MMPs-2, -3, -7, -10, -9, -11 and enhances the metastatic potential of fibrosarcoma cells when implanted in immunodeficient mice. The Sod2-dependent increases in AP-1 and SP-1 DNA-binding activity, MMP-1 promoter activity, general MMP expression, and collagen degradation can be reversed by the hydrogen peroxide-detoxifying enzyme, catalase. CONCLUSION: MMPs play a critical role in the process of stromal invasion and metastasis, and these findings suggest that the association between increased Sod2 and poor prognosis in certain cancers may be attributed to elevated MMP production.

Animals↗

PubMed2002

A peptide derived from alpha-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen.

An 8-mer peptide (EMTOVNOG) derived from alpha-fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be resistant to tamoxifen in vivo. Peptide completely prevented the xenograft growth of this tamoxifen-resistant subline of MCF-7. Neither peptide nor tamoxifen was effective in slowing the xenograft growth of the estrogen-receptor-negative MDA-MB-231 human breast cancer. A worrisome side effect of tamoxifen is its hypertrophic effect on the uterus. In this study, tamoxifen was shown to stimulate the growth of the immature mouse uterus in vivo, and the peptide significantly inhibited tamoxifen's uterotrophic effect. The mechanism of action of peptide is different from that of tamoxifen in that the peptide does not interfere with the binding of [(3)H]estradiol to the estrogen receptor. In conclusion, alpha-fetoprotein-derived peptide appears to be a novel agent that interferes with the growth of tamoxifen-sensitive as well as tamoxifen-resistant estrogen-receptor-positive human breast cancers; it inhibits the uterotrophic side effect of tamoxifen and, thus, it may be useful in combination with or in place of tamoxifen for treatment of estrogen-receptor-positive human breast cancers.

Animals↗

PubMed2002

Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line.

PURPOSE: Resveratrol (Calbiochem, La Jolla, California) is a naturally occurring stilbene reported to cause apoptosis in various cultured cancer cells. In the current study the effect of resveratrol was determined in the androgen insensitive DU 145 prostate cancer cell line. Induction of apoptosis and activation of apoptosis related signal transduction pathways were measured. MATERIALS AND METHODS: DU 145 cells were treated with resveratrol and apoptosis was measured by determining nucleosome content. Activation of mitogen activated protein kinase (MAPK) (extracellular signal-regulated kinase 1/2), p53 content and serine-15 phosphorylation of p53 were measured by immunoblot. Electrophoretic mobility shift assay of p53 binding to DNA, and measurement of p21 and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were also done. RESULTS: Resveratrol induced apoptosis in DU 145 cells. The stilbene activated MAPK and caused increased abundance of p53 and serine-15 phosphorylated p53. Resveratrol induced serine-15 phosphorylation of p53 was blocked by PD 98059 (Calbiochem), a MAPK kinase inhibitor, implicating MAPK activation in the phosphorylation of p53. PD 98059 also inhibited resveratrol induced apoptosis. These results suggest that apoptosis induction by resveratrol in DU 145 cells requires serine-15 phosphorylation of p53 by MAPK. Inhibition of MAPK dependent serine-15 phosphorylation resulted in reduced p53 binding to a p53 specific oligonucleotide on electrophoretic mobility shift assay. Pifithrin-alpha (Calbiochem), a p53 inhibitor, blocked resveratrol induced serine-15 phosphorylation of p53 and p53 binding to DNA. Resveratrol caused a p53 stimulated increase in p21 messenger RNA. Transfection of additional wild-type p53 into DU 145 cells induced apoptosis, which was further enhanced by resveratrol treatment. CONCLUSIONS: Resveratrol causes apoptosis in DU 145 prostate cancer cells. This action depends on the activation of MAPK, increase in cellular p53 content, serine-15 phosphorylation of p53 and increased p53 binding to DNA.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Assessing diabetes patients' healthcare needs.

Pharmacists who possess the proper skills and knowledge can intervene with patients in a proactive manner by initiating a dialogue at the point of dispensing medication. After patients complete the DPAQ and the pharmacist assesses the information, a plan of care is developed. Proper documentation (e.g., using the SOAP format) is the first and most important step in caring for patients with diabetes. Such encounters impact on the level of care provided and are professionally and financially rewarding for the pharmacist.

Delivery of Health Care↗

PubMedDate not supplied

Evaluating process changes in a pediatric hospital medication system.

This article describes a process change designed to increase the safety of prescribing and interpreting complex order sets. All chemotherapy orders written for pediatric oncology patients at a major teaching hospital in the Eastern United States and the affiliated ambulatory clinic from June 1998 through February 2000 (n = 1792) were reviewed to evaluate a new process for communication of chemotherapy orders. The multidisciplinary check (MDC) is a forum where all disciplines simultaneously review and change complex order sets. Evaluation of the MDC included monthly completion rate and classification of changes made to orders at MDC. Over the study period, 96% of eligible orders received a multidisciplinary check, and 44% were changed. The most common change was to clarify discrepancies between the order and the protocol. Changes were made to avoid medication errors in 99 of 451 orders. Changes to avoid medication errors were more likely to involve nonchemotherapy medications. The MDC is an efficient and feasible process to increase safety at the beginning of the medication system.

Antineoplastic Agents↗