Biomedical subjects

L G Boros

Publications and source records attributed to L G Boros.

32 records · Page 2Linked to original sources

PubMed1998

Variable effect of streptozotocin-diabetes on the growth of hamster pancreatic cancer (H2T) in the Syrian hamster and nude mouse.

BACKGROUND: Streptozotocin-diabetes prevents induction of pancreatic tumors in several animal models and inhibits the growth of established human pancreatic cancer implants in nude mice. However, it also promotes growth of the hamster pancreatic cancer cell line, H2T, in the Syrian hamster. To test the hypothesis that these contradictory effects are due to tumor host differences, the growth of the H2T cell line was examined in the streptozotocin-diabetic nude mouse. METHODS: H2T cells were implanted subcutaneously into streptozotocin-diabetic nude mice (n = 10) and untreated control mice (n = 10). After 21 days, tumors were excised and weighed. Plasma insulin and somatostatin were determined by radioimmunoassay. RESULTS: After 3 weeks, tumors in the control group weighed 118 mg and tumors in the diabetic group weighed 28 mg (p < 0.001). Plasma insulin was significantly decreased in the streptozotocin-treated animals compared with control animals (insulin, 23 microU/ml vs 31 microU/ml; p < 0.001). In contrast, somatostatin was significantly elevated in the streptozotocin-diabetic group compared with the control group (somatostatin, 179 pg/ml versus 54 pg/ml, p < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd, 15.5 nmol/L), and somatostatin (Kd, 2.5 nmol/L) on the H2T cells. In an in vitro cell proliferation assay, cell division was promoted by insulin (p < 0.01, maximum +11%) and inhibited by somatostatin (p < 0.01, maximum -18%). CONCLUSIONS: The variable effect of streptozotocin-diabetes on pancreatic cancer growth is due to differences in the tumor host. The growth of pancreatic cancer, particularly in streptozotocin-diabetic nude mice, may be influenced by gut peptides in a receptor-dependent fashion.

Animals↗

PubMed1997

Oxythiamine and dehydroepiandrosterone inhibit the nonoxidative synthesis of ribose and tumor cell proliferation.

This study investigates the significance of the glucose-6-phosphate dehydrogenase (G6PD) catalyzed oxidative and the transketolase (TK) catalyzed nonoxidative pentose cycle (PC) reactions in the tumor proliferation process by characterizing tumor growth patterns and synthesis of the RNA ribose moiety in the presence of respective inhibitors of G6PD and TK. Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-(13)C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%). Five days of treatment with the TK inhibitor oxythiamine (OT) and the G6PD inhibitor dehydroepiandrosterone-sulfate (0.5 microM each) exerted a 39 and a 23% maximum inhibitory effect on cell proliferation in culture, which was increased to 60% when the two drugs were administered in combination. In vivo testing of 400 mg/kg OT or dehydroepiandrosterone-sulfate in C57BL/6 mice hosting Ehrlich's ascitic tumor cells revealed a 90.4 and a 46% decrease in the final tumor mass after 3 days of treatment. RNA ribose fractional synthesis through the TK reaction using metabolites directly from glycolysis declined by 9.1 and 23.9% after OT or the combined treatment, respectively. Nonoxidative PC reactions play a central regulating role in the carbon-recruiting process toward de novo nucleic acid ribose synthesis and cell proliferation in vitro and in vivo. Therefore, enzymes or substrates regulating the nonoxidative synthesis of ribose could also be the sites to preferentially target tumor cell proliferation by new anticancer drugs.

Animals↗

PubMed1997

Dehydroepiandrosterone-sulfate inhibits pancreatic carcinoma cell proliferation in vitro and in vivo.

BACKGROUND: Dehydroepiandrosterone-sulfate (DHEA-S) is a potent inhibitor of glucose-6 phosphate dehydrogenase, the rate limiting enzyme of the hexose monophosphate shunt, a biochemical pathway that provides substrate for DNA synthesis in neoplastic tissue. DHEA-S has been shown to inhibit the growth of neoplasms arriving from human skin, lung, colon, and mammary tissue. This study evaluates the effect of DHEA-S on human pancreatic cancer cell lines in vitro and in vivo. METHODS: In vitro, the human pancreatic adenocarcinoma cell lines MiaPaCa-2, Capan-1, Capan-2, CAV and Panc-1 were treated with concentrations of 1.9 mumol/L to 1000 mumol/L DHEA-S in 1% dimethylsulfoxide (DMSO) for 5 consecutive days. Cell proliferation was determined by a nonradioactive cell proliferation assay and compared with DMSO treated controls. In vivo testing was performed by inoculating two cell lines, MiaPaCa-2 and Panc-I, into the flank of 40 male nude athymic mice in four study groups. After 1 week of growth, 667 mg/kg DHEA-S in 1% DMSO or 0.2 ml 1% DMSO alone in the control group was administered by daily intraperitoneal injection. Body weight and tumor size was recorded weekly, and tumor weight was measured after 3 weeks of treatment. RESULTS: In vitro cell proliferation was decreased in the five cell lines by 36% to 62% of controls (p < 0.001) at 500 mumol/L DHEA-S. In vivo, after 2 weeks, tumor size was only 76% (p < 0.008) and 67% (p < 0.005) of the controls. After 3 weeks of treatment, tumor size was 73% (p < 0.001) and 53% (p < 0.001) of controls, and tumor weight was decreased by 73% in MiaPaCa-2 (p < 0.001) and 66% in Panc-1 (p < 0.001). Radioimmunoassay measurements of DHEA-S and testosterone from DHEA-S treated mouse plasma showed a significant increase in circulating levels of these hormones. CONCLUSIONS: DHEA-S achieves high serum levels after intraperitoneal injection without elevation of serum testosterone levels and produces no significant toxicity. Treatment with DHEA-S results in a significant reduction of proliferation of human pancreatic cancer cells in culture and when grown as subcutaneous tumors in athymic nude mice.

Adenocarcinoma↗

PubMed1996

Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors.

Type-II diabetes is a risk factor for pancreatic cancer. In addition, diabetic patients present with more advanced tumors and have shortened survival compared to stage-matched counterparts. We hypothesize that the diabetic endocrine milieu, particularly elevated plasma insulin, favors pancreatic cancer growth. This study examines six human pancreatic cancer cell lines for the presence of insulin receptors and the influence of insulin on tumor proliferation. Classical competitive binding assays are performed using [125I insulin. Cell proliferation assays are conducted over 3 days on cultured cell lines (n = 6 replicates) with increasing concentrations of insulin. Insulin receptors are demonstrated on all six cell lines and dose dependent increases in cell proliferation (15-120% of control) are demonstrated in response to insulin. Patients with type-II diabetes hypersecrete insulin. The presence of high-affinity insulin receptors and dose dependent increases in pancreatic cancer cell proliferation with insulin supports the hypothesis that insulin may be an important tumor growth promoter in diabetes, particularly if paracrine mechanisms are involved. Additional study is required to determine whether other islet peptides altered in diabetes influence tumor growth and whether elevated plasma insulin favors pancreatic cancer induction.

Adenocarcinoma↗

PubMed1995

GI hormonal changes in diabetes influence pancreatic cancer growth.

Streptozotocin diabetes prevents induction of pancreatic tumors in several animal models, suggesting a pivotal role for islet cell products in the pathogenesis of pancreatic cancer. To test the hypothesis that altered gastrointestinal peptide levels in streptozotocin diabetes influence tumor growth, human pancreatic cancer cells (MIA PaCa-2) were implanted subcutaneously into streptozotocin diabetic nude mice. After 3 weeks, tumors in the control group weighed 43 mg and tumors in the diabetic group weighed 12 mg (P < 0.001). Plasma insulin and IGF-1 levels were significantly decreased in the streptozotocin-treated animals compared to those of control (insulin: 23 microU/ml vs 31 microU/ml, P < 0.001; IGF-1: 254 ng/ml vs 324 ng/ml, P < 0.001). In contrast, somatostatin and glucagon were significantly elevated in the streptozotocin diabetic group relative to control levels (somatostatin: 179 pg/ml vs 54 pg/ml, P < 0.001; glucagon: 290 pg/ml vs 134 pg/ml, P < 0.001). Competitive binding studies revealed specific cell surface receptors for insulin (Kd = 15.5 nM), IGF-1 (Kd = 30.0 nM), and somatostatin (Kd = 2.5 nM) on the MIA PaCa-2 cells. Receptors for glucagon were absent. In an in vitro cell proliferation assay, cell division was promoted by insulin (P < 0.01, max + 11%) and IGF-1 (P < 0.01, max + 10%). Somatostatin inhibited cell division (P < 0.01, max - 18%). No effect was seen with glucagon. The growth of pancreatic cancer, particularly in diabetes, may be influenced by gut peptides in a receptor-dependent fashion.

Animals↗

PubMed1995

Reversal of enhanced pancreatic cancer growth in diabetes by insulin.

BACKGROUND: Epidemiologic and animal studies have linked pancreatic cancer growth with both diabetes and fat intake. This study examined the influence of insulin treatment on pancreatic cancer growth in diabetes. Diabetes-induced elevations in levels of glucose and free fatty acids were correlated with enhanced tumor growth both in vivo and in vitro. METHODS: Hamsters were divided into three groups: control (n = 15), streptozocin-diabetic (n = 20), or insulin-treated diabetic (n = 20). Diabetes was induced with streptozocin and treated with a continuous subcutaneous infusion of insulin delivered via osmotic pumps. Five x 10(5) H2T hamster pancreatic cancer cells were implanted into the cheek pouch. Levels of plasma glucose and fatty acids were measured, and their effect on H2T cell division was assessed in vitro with a spectrophotometric cell proliferation assay. RESULTS: Levels of plasma glucose and fatty acids were elevated in streptozocin-diabetic animals and normalized with insulin treatment. After 21 days of growth, tumor weight was 36 mg in the control group, 156 mg in the diabetic group (p < 0.01 versus other groups), and 33 mg in the insulin-treated diabetic group. In vitro dose-dependent promotion of cell growth was shown for glucose (250%), linoleic acid (287%), linolenic acid (169%), and oleic acid (98%). CONCLUSIONS: Insulin ameliorated enhanced tumor growth in this model of diabetes. Glucose and free fatty acids mobilized during diabetes may serve as fuel for established pancreatic cancers.

Animals↗

PubMed1994

Granulocyte-macrophage colony stimulating factor gene expression and function during tumor promotion.

Although recent evidence suggests that granulocyte-macrophage colony stimulating factor (GM-CSF) plays a role in cutaneous inflammation induced by topical exposure of phorbol ester tumor promoters to murine epidermis, there is little information available on the temporal sequence of gene expression of this cytokine over the time course of tumor promotion or about its function in this process. The goal of the present studies was to examine the potential role of GM-CSF in tumor promotion in SENCAR mice. Competitive reverse transcriptase polymerase chain reaction (RT-PCR) studies demonstrated that a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA; 2 micrograms, 10 micrograms) to the dorsal epidermis of SENCAR mouse skin stimulated a dose and time dependent GM-CSF gene expression that was upregulated at 1 h after TPA exposure, peaked at 3 h and declined at 12 h. Although treatment with 7',12'-dimethylbenz[a]anthracene (DMBA) did not stimulate GM-CSF gene expression, GM-CSF gene expression was elevated in epidermal tissue isolated from SENCAR mice treated with a single application of 10 nmol DMBA followed by multiple applications of 2 micrograms TPA over a 1-22 week time course. Immunochemical and autoradiographic studies demonstrated that GM-CSF protein was produced by suprabasal keratinocytes, interfollicular cells, nonproliferating papilloma cells and leukocytes within the dermis. Intraperitoneal injection of recombinant (r) GM-CSF into SENCAR mice at 2 h prior to topical application of 10 micrograms TPA induced a significant increase in epidermal keratinocyte proliferation, leukocyte infiltration into the dermis, hydroperoxide production by circulating neutrophils and chemotactic activity present within the plasma at 24 h compared to treatment with only 10 micrograms TPA. Intravenous injection of anti-GM-CSF antibodies significantly inhibited both local and systemic inflammatory events induced by topical application of TPA. The present studies suggest that GM-CSF has a broad spectrum of activity with at least two target cell populations, epidermal keratinocytes within the proliferative compartment and leukocytes. This cytokine is actively transcribed during the tumor promotion process, acts as a signal peptide that stimulates epidermal proliferation, primes circulating neutrophils to produce hydroperoxide and regulates leukocyte migration.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1993

Interleukin-1 alpha gene expression and localization of interleukin-1 alpha protein during tumor promotion.

Treatment of the dorsal epidermis of SENCAR mice with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced a time- and dose-dependent stimulation of interleukin-1 alpha (IL-1 alpha) gene expression. Levels of IL-1 alpha mRNA were elevated as early as 15 min and peaked at 3-4 h after a single application of TPA (2 micrograms or 10 micrograms). IL-1 alpha gene expression increased in epidermal tissue isolated from SENCAR mice at 1, 3, 6, 10, 16, and 22 wk after a single treatment with 10 nmol 7,12-dimethylbenz[a]anthracene (DMBA) and subsequent twice-weekly application of 2 micrograms TPA. IL-1 alpha-immunoreactive protein was specifically localized within suprabasal keratinocytes in cutaneous tissue isolated from mice treated with DMBA-TPA for 1-22 wk and in nonproliferating cells located within papilloma tissue isolated from SENCAR mice at 22 wk after initiation and promotion. Basal cells within hyperplastic epidermis did not produce IL-1 alpha-immunoreactive protein. DMBA treatment alone did not induce IL-1 alpha gene expression. Injection of IL-1 alpha-specific antibodies (50 micrograms) into SENCAR mice via the tail vein 2 h before treatment with TPA (2 micrograms or 10 micrograms) significantly (P < 0.05) inhibited the skin thickening usually observed 24 h after treatment with TPA. Autoradiography studies showed that injection of anti-IL-1 alpha antibodies inhibited incorporation of [methyl-3H]thymidine by keratinocytes within the epidermis and by cells within hair follicles. It also inhibited neutrophil infiltration into the dermis, which usually results from topical application of TPA. These data suggest that IL-1 alpha is a pivotal cytokine produced by specific subpopulations of epidermal keratinocytes and that IL-1 alpha primarily regulates the epidermal proliferative response of a distinctly separate population of keratinocytes after topical exposure of murine epidermis to TPA and secondarily modulates neutrophil migration into the dermis. Consequently, manipulation of IL-1 alpha may be a way to attenuate or abrogate the cutaneous response to TPA by altering keratinocyte proliferation, the resultant hyperplasia, and a portion of the inflammatory response characterized by dermal infiltration of neutrophils.

Acetone↗

PubMed1993

An automatized computer-method utilizing Procomm Plus and DataEase (4.2) PC and SAS (6.06) mainframe software for isolated, perfused guinea-pig heart studies.

A powerful, time sharing and automatized method of a comprehensive data analysis for isolated, perfused guinea-pig heart studies is described. Data are collected using DataEase PC software (version 4.2) into forms with data fields specified for vital parameters consistently recorded in isolated, perfused heart studies (HR, CBF, PEAKPRESSURE, DPDT, MVO2). After running, DataEase reports the data and information is uploaded to an IBM 3081D mainframe computer on each day of heart experiment and data collection. The uploading process, the data archival and the statistical analyses are automatized by Procomm Plus commands written in Aspect Source Program (.ASP) Files for logging, data transforming and file management procedures. The ASPCOMP.EXE compiler compiles these .ASP files into Aspect Script eXecutable (.ASX) programs, which run on the PC in our laboratory and activate WYLBUR (IBM 3081D Batch-job service and Command file processor) edited files in the mainframe's electronic devices then upload, backup and save data into these files. SAS EXE files containing program instructions for the data analyzing system are then forced by Procomm Plus to operate over the data just uploaded. SAS reads the DATA files by its INFILE facility and performs comprehensive statistical analyses and produces hard output including graphics and JOB reports of dose-response- and logaritmic scale curves for delivery to team members. This computerized and automatized method developed for isolated, perfused guinea-pig heart studies is capable of performing multiple file transfer, sophisticated statistical analyses and graphic procedures after one keystroke on the PC (Alt-F5 in Procomm Plus section) and also facilitates a consistent and convenient method for planning, controlling and standardizing experiments. The method is based on an interactive computer conversation between the PC in the laboratory and the remote's WYLBUR editor. No human presence is needed; however, in case of failure, Procomm Plus gives one of the team members supervising the system a phone call in order to get human help.

Animals↗

PubMed1992

CD-ROM source data uploaded to the operating and storage devices of an IBM 3090 mainframe through a PC terminal.

A powerful method of processing MEDLINE and CINAHL source data uploaded to the IBM 3090 mainframe computer through an IBM/PC is described. Data are first downloaded from the CD-ROM's PC devices to floppy disks. These disks then are uploaded to the mainframe computer through an IBM/PC equipped with WordPerfect text editor and computer network connection (SONNGATE). Before downloading, keywords specifying the information to be accessed are typed at the FIND prompt of the CD-ROM station. The resulting abstracts are downloaded into a file called DOWNLOAD.DOC. The floppy disks containing the information are simply carried to an IBM/PC which has a terminal emulation (TELNET) connection to the university-wide computer network (SONNET) at the Ohio State University Academic Computing Services (OSU ACS). The WordPerfect (5.1) processes and saves the text into DOS format. Using the File Transfer Protocol (FTP, 130,000 bytes/s) of SONNET, the entire text containing the information obtained through the MEDLINE and CINAHL search is transferred to the remote mainframe computer for further processing. At this point, abstracts in the specified area are ready for immediate access and multiple retrieval by any PC having network switch or dial-in connection after the USER ID, PASSWORD and ACCOUNT NUMBER are specified by the user. The system provides the user an on-line, very powerful and quick method of searching for words specifying: diseases, agents, experimental methods, animals, authors, and journals in the research area downloaded. The user can also copy the TItles, AUthors and SOurce with optional parts of abstracts into papers under edition. This arrangement serves the special demands of a research laboratory by handling MEDLINE and CINAHL source data resulting after a search is performed with keywords specified for ongoing projects. Since the Ohio State University has a centrally founded mainframe system, the data upload, storage and mainframe operations are free.

CD-ROM↗

PubMedDate not supplied

Interleukin-1alpha gene expression during wound healing.

Interleukin-1alpha is known to be constitutively produced by epidermal keratinocytes under normal conditions, and injection of this cytokine enhances wound reepithelialization. However, no studies have characterized the temporal sequence of interleukin-1alpha gene expression over the time course of wound healing, and the cellular sources of this cytokine have not been identified. In the present studies, levels of interleukin-1alpha messenger RNA in wound tissue isolated from SKH-1 hairless mice were characterized and the cells that produced interleukin-1alpha immunoreactive protein over a 10-day time course of wound healing were defined. A time-dependent upregulation in interleukin-1alpha gene expression occurred immediately (4 hours) after a full-thickness wound was made, which represented a four-fold increase over levels of cytokine gene expression detected in nonwounded skin. Upregulation of cytokine gene expression correlated with an immediate increase in plasma interleukin-1alpha levels and was followed by an increase in interleukin-1alpha immunoreactive protein localized to keratinocytes within the leading edge of the wound and epidermis, as well as to neutrophils within the dermis. The rapid increase in local and systemic interleukin-1alpha levels correlated with the infiltration of a significant number of neutrophils into the wound site and with the proliferation of both basal keratinocytes and dermal fibroblasts. Given the known ability of interleukin-1alpha to regulate proliferation and migration of epidermal keratinocytes and to indirectly induce leukocyte chemotaxis, the results of the present studies suggest that interleukin-1alpha may be an important cytokine with both local and systemic actions that are linked to the initiation of critical cellular events early in wound healing.

Journal Article↗

PubMedDate not supplied

Characterization of a murine model of acute lung injury (ALI): a prominent role for interleukin-1.

This report describes a model developed to study local and systemic events that occur as a result of acute lung injury (ALI). C57BL/6J mice were injected with a single intravenous dose (2, 4, and 6 micrograms) of 12-O-tetradecanoylphorbol-13-acetate (TPA). At 1, 2, 4, 12, 24, and 48 h, after injection, plasma was collected by sinus orbital puncture, bronchoalveolar lavage (BAL) was performed and cells and fluid were collected, lungs were perfused, and pulmonary tissue was isolated and processed for histological, immunochemical, and gene expression studies. The results indicate a dose-dependent increase in animal distress and a decrease in survival. TPA induced an early systemic response, reflected as an initial decrease in numbers of peripheral blood neutrophils at 1 h, followed at 2 h by a sustained increase. There was dose- and time-dependent increase in IL-1 beta mRNA synthesis, detected using RT-PCR, and in immunoreactive IL-1 alpha produced by both tissue-fixed pulmonary cells and cells within alveolar spaces. Infiltration of neutrophils into pulmonary tissue and increased protein content in BAL fluid was detected 2 h after injection of TPA. Disruptions in pulmonary architecture accompanied by the presence of highly vacuolated macrophages within the alveolar spaces and interstitial tissue were evident after IV injection of TPA. The study shows that injection of TPA induces reproducible dose- and time-dependent alterations in cell types, numbers, state of activation, and production of soluble mediators in the peripheral circulation within BAL and pulmonary tissue. Thus, this model offers a means to examine the cellular basis for the local and systemic alterations observed during ALI.

Animals↗

PubMedDate not supplied

Population thiamine status and varying cancer rates between western, Asian and African countries.

The role of food supplements in the form of vitamins has not been extensively investigated in relation to varying cancer rates between populations of different geographical regions. New data indicate that thiamine (vitamin B1), a common food supplement in Western food products, is directly involved in nucleic acid ribose synthesis of tumor cells in its biologically activated form through the non-oxidative transketolase catalyzed pentose cycle reaction. Whether thiamine plays a role in increased cancer rates in the Western World by enhancing tumor cell proliferation, while increased consumption of thiaminase rich food limiting thiamine availability protects against common malignancies in Asia and Africa has not been evaluated. In the Western World, thiamine is a popular vitamin supplement in the form of tablets and it is also added to basic food items such as milled flour, cereals, peanut butter, refreshment drinks and pastas. On the contrary, thiaminase, the natural thiamine-degrading enzyme, is abundantly present in raw and fermented fish, certain vegetables and roasted insects consumed primarily in Africa and Asia. Excess thiamine supplementation in common food products may contribute to the increased cancer rates of the Western World.

Africa↗

PubMedDate not supplied

Thiamine supplementation to cancer patients: a double edged sword.

The objectives of this review are to (a) explain the mechanism by which thiamine (vitamin B1) promotes nucleic acid ribose synthesis and tumor cell proliferation via the nonoxidative transketolase (TK) pathway; (b) estimate the thiamine intake of cancer patients and (c) provide background information and to develop guidelines for alternative treatments with antithiamine transketolase inhibitors in the clinical setting. Clinical and experimental data demonstrate increased thiamine utilization of human tumors and its interference with experimental chemotherapy. Analysis of RNA ribose indicates that glucose carbons contribute to over 90% of ribose synthesis in cultured cervix und pancreatic carcinoma cells and that ribose is synthesized primarily through the thiamine dependent TK pathway (> 70%). Antithiamine compounds significantly inhibit nucleic acid synthesis and tumor cell proliferation in vitro and in vivo in several tumor models. The medical literature reveals little information regarding the role of the thiamine dependent TK reaction in tumor cell ribose production which is a central process in de novo nucleic acid synthesis and the salvage pathways for purines. Consequently, current thiamine administration protocols oversupply thiamine by 200% to 20,000% of the recommended dietary allowance, because it is considered harmless and needed by cancer patients. The thiamine dependent TK pathway is the central avenue which supplies ribose phosphate for nucleic acids in tumors and excessive thiamine supplementation maybe responsible for failed therapeutic attempts to terminate cancer cell proliferation. Limited administration of thiamine and concomitant treatment with transketolase inhibitors is a more rational approach to treat cancer.

Antineoplastic Agents↗