| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
Laboratory of Experimental Neuroendocrinology/Oncology, Bassett Research Institute, Cooperstown, New York 13326
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
These data suggested that 13-HODE formation is required for LA-dependent growth in hepatoma 7288CTC in vivo. In this study, we examined the role of LA uptake and 13-HODE release on growth in vivo and the effect of 13-HODE on [3H] thymidine incorporation during perfusion in situ. The results, which showed a requirement of 13-HODE for both activities, provide evidence that 13-HODE is the mitogenic factor in LA-dependent growth in hepatoma 7288CTC. This is the first demonstration of a direct mitogenic effect of 13-HODE in a solid tumor.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Animals, Diets, and Tumor Implantation and Growth.
Male Buffalo (BUF/NCR) rats (4–5 weeks of age) weighing 35– 75 g were purchased from Charles River Laboratories (Kingston, NY). Male Sprague Dawley rats weighing 150–200 g were purchased from Harlan Sprague-Dawley (Indianapolis, IN). Except for two rat groups described below, all animals were given free access to water and an EFA-replete diet (Prolab rat, mouse, hamster 1000 formula; Agway, Syracuse, NY). Duplicate determinations of six separate batches showed that this diet contained 4.1 g of total fatty acids/100 g diet composed of 1.3% myristic acid (14:0), 22.7% palmitic acid (C16:0), 2.6% palmitoleic acid (C16:1), 12.3% stearic acid (C18:0), 33.1% oleic acid (C18:1n9), 25.7% LA (C18:2n6), and 0.2% arachidonic acid (C20:4n6). Trace amounts of other unidentified fatty acids accounted for 2.1%. Two groups of Buffalo and Sprague Dawley rats were given free access to water and a semipurified, fat-free, EFAD diet that contained 0.03 g of LA/100 g diet and small amounts of non-EFAs derived from the corn starch component of the diet (5)
. All rats were subjected to alternate 12-h periods of dark and light (6:00 a.m.–6:00 p.m.) throughout the experiments. There was no light contamination during the dark phase. Temperature and humidity were maintained at 23°C and 40–60%, respectively.
Tissue-isolated Morris hepatoma 7288CTC was implanted in male Buffalo rats on the tip of a vascular stalk formed from the superficial epigastric artery and vein, as described previously (9) . The tumor implant and vascular stalk were enclosed within a parafilm envelope, placed in the inguinal fossa, and the skin incision was closed. Vascularization of the implant was limited to new vessel connections with the epigastric artery and vein; subsequent tumor growth was s.c. The latent period from implantation to first evidence of tumor growth was recorded, and subsequent tumor size was estimated every 2–3 days from measurements made through the skin (10) . These data were converted to weights, as described previously (10) , and growth rates (g/day) were calculated by linear regression. Tumor-bearing rats were treated with NDGA (10 µ M) supplied in the drinking water.
Tumor Arteriovenous Difference Measurements in Vivo and during Perfusion in Situ.
Arteriovenous difference measurements across tissue-isolated tumors in vivo were performed when the estimated tumor weight was 4–6 g. Experiments were scheduled between 8:00 a.m. and 10:30 a.m. after a normal nocturnal feeding period. Procedures for anesthesia and heparinization of the host rat, for surgical preparation of the tumor and for collection of arterial and tumor venous blood samples, were performed as described previously (5
, 6
, 9)
. Anesthetized host rats were breathing air unassisted, and body temperature was maintained at 37°C with a heating pad (below) and a heat lamp (above). Blood flow from the tumor vein, which typically ranged from 0.09–0.12 ml/min, was collected passively. Both arterial and tumor venous blood samples were collected into tubes chilled in ice. Separate samples were collected simultaneously for measurement of hematocrit and for analysis of blood gases and pH.
Detailed descriptions of the surgical and technical procedures for the perfusion of tissue-isolated tumors in situ were described previously (6 , 11, 12, 13) . Donor blood (about 50 ml) for perfusion was collected between 8:00 a.m. and 10:00 a.m. from heparinized adult male Sprague Dawley rats weighing 250–300 g and was filtered through cheesecloth and stored, under mineral oil, in a chilled, stirred reservoir packed in ice. The whole blood perfusate was pumped from the reservoir using a peristaltic pump and passed through a heat-exchanger that warmed the blood to 37°C and then an artificial lung that contained a mixture of air and 5% CO2 saturated with water at 37°C. The proportion of the components and the flow of the gas mixture was adjusted using a dual-flow regulator to maintain pO2, pCO2, and pH values of 130 mm Hg, 30 mm Hg, and 7.4, respectively, in the arterial blood entering the tumor (13) . The vascular connections (epigastric artery and vein) between tumor and host were severed after attachment of the tumor to the arterial catheter from the reservoir. The host was sacrificed, but the temperature of the hindquarters containing the tumor were monitored and maintained at 37°C during the perfusion (13) . The peristaltic pump was adjusted to provide a tumor venous blood flow of about 0.1 ml/min. Hemoconcentration of the tumor venous blood occurred across the tumor (9) to the same extent as that observed in vivo.
Perfusions were typically for 120–150 min and were preceded by a 30-min perfusion period (no sample collections) to allow steady-state conditions to be established. Arterial and tumor venous blood for fatty acid, 13-HODE, 13-KODE, and blood gas analyses and hematocrit were collected at 30-min intervals. Depending on the experiment, donor blood was supplemented with 13-HODE, 13-KODE, 9-HODE, or NDGA (10 µM), singly or in combination. 13-HODE, 13-KODE, and 9-HODE were dissolved in plasma obtained by centrifugation of a portion of the pooled donor blood; the cellular fraction was added back before the addition to the reservoir. An aqueous solution of NDGA was added directly to the pooled donor whole blood either before or during the perfusion to give a final concentration of 10 µM in the reservoir. Values for rates of supply, uptake, and release of fatty acids and LA metabolites were calculated as described previously (9) and are expressed as ng or µ g/min/g wet weight tumor. All procedures involving animals and animal preparations were approved by the Institutional Animal Care and Use Committee.
Incorporation of [3H]thymidine into DNA was performed by injecting 20 µl of a solution containing 2 µCi [methyl-3H]thymidine/g estimated tumor weight into the arterial blood line 20 min before the end of the perfusion (6 , 12) . The [3H]thymidine made one pass through the tumor; unincorporated radioactivity was washed out of the perfused tumor during the remaining 20 min of perfusion. Radioactivity incorporated into tumor DNA was measured by liquid scintillation using internal standardization and is reported as dpm/µg tumor DNA (6 , 12) . Tumor DNA was measured in 20% (w/w) homogenates fluorometrically using Hoechst dye 33258 and the procedure described in Technical Bulletin #119, Hoefer Scientific Instruments (San Francisco, CA).
Lipid Extraction and Gas Chromatography.
Plasma and dietary lipids were extracted as described previously (5
, 6)
using the procedure of Folch et al. (14)
. Internal standard (100 µg of heptadecanoic acid) was added before extraction. Lipid extracts were saponified in methanolic-NaOH (0.5 mM) for 5 min at 100°C, and the fatty acids were methylated using boron triflouride reagent (14%) for 2 min at 100°C. Fatty acid methyl esters were measured using a Hewlett-Packard (Palo Alto, CA) gas chromatograph model 5890A equipped with a flame-ionization detector, electronic integrator (model 3396A), and autoinjector (model 7673S). Separations were performed using a 0.25 mm x 30-m capillary column (model 2330; Supelco Inc., Bellefonte, PA) at 190°C with helium as the carrier gas (linear gas rate, 19 cm/sec). Fatty acid methyl esters were identified by their retention times compared with known standards. The values designated for total plasma fatty acids represent the sum of the seven major fatty acids (myristic, palmitic, palmitoleic, stearic, oleic, LA, and arachidonic acids) present as free fatty acids, cholesterol esters, triacylglycerols, phospholipids, and other plasma lipids (15)
and are expressed as µg or mg liter plasma.
Measurement of 13-HODE and 13-KODE.
Arterial and tumor venous blood plasma samples (0.2–0.6 ml) collected in vivo or during perfusion in situ were analyzed by HPLC (5)
. The internal standard was 1 µg of either (±) 5-HETE or 15-hydroxy-9-oxoprostatrienoic acid for analysis of 13-HODE or 13-KODE, respectively. The sample was acidified with 50 µl glacial acetic acid and extracted on a C18-PrepSep column (Fisher Scientific, Pittsburgh, PA), prewashed with 10 ml of methanol and 10 ml of water. The lipids were eluted with 4 ml of methanol and evaporated to dryness under nitrogen. The residue was taken up in 30% methanol, and the metabolites were separated on a C18Ultrasphere column (5 µm; 4.6 x 250 mm; Altex Scientific, Beckman Instruments, Berkeley, CA) using an ISCO (Lincoln, NE) model 2350 pump with 80% methanol/20% water/0.01% acetic acid as the mobile phase at a flow rate of 1.0 ml/min. The eluent was monitored at 235 nm and 279 nm using an ISCO variable wavelength detector, and the peaks were integrated and quantified using the ISCO ChemResearch software program. The extinction coefficients used were: 9- and 13-HODE, 23,000; 13-KODE, 22,300; and 5-HETE, 27,000. Ultraviolet absorption spectra of samples and standards were recorded using a Hewlett-Packard (Palo Alto, CA) 8452A diode array spectrophotometer with methanol as solvent and blank.
Statistical Analysis.
Results are expressed as mean ± SD. The effects of NDGA, 13-HODE, and 13-KODE alone and in combination on incorporation of [3H]thymidine into tumor DNA were examined by one-way ANOVA. Differences were considered to be significant at P < 0.05. When differences were detected, the means were compared using Student-Newman-Keuls multiple comparison test (16)
.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Fatty Acid Uptake and 13-HODE Release in Hepatoma 7288CTC during Perfusion in Situ: Effects of NDGA.
The techniques for tumor perfusion in situ described in "Methods" were designed to reproduce the in vivo condition as closely as possible. Tumor-bearing and donor rats were given free access to laboratory chow and water, and all experiments were performed between 8:00 a.m. and 10:30 a.m. after a normal overnight feeding period. Perfusions typically lasted 120–150 min. Fig. 1
shows the steady-state rates of LA and total fatty acid uptake observed during perfusion in situ of a single hepatoma 7288CTC. Uptakes of total fatty acids and of LA alone were constant during the 150-min perfusion. Release of 13-HODE into the tumor venous blood was steady until the addition of NDGA. 13-HODE is unmeasureably low in arterial blood and is not generated in the perfusion apparatus in the absence of a tumor. The addition of the lipoxygenase inhibitor NDGA (10 µM) to the reservoir donor blood at 60 min abolished 13-HODE release but affected neither LA nor total fatty acid uptake. About 30 min were required for the NDGA-containing reservoir blood to pass through the 37°C water bath, artificial lung, and the tumor.
|
. [3H] thymidine incorporation and DNA contents of control and NDGA-treated tumors grown in and perfused with donor blood from EFA-replete rats and the effects of exogenous 13-HODE, 13-KODE, or 9-HODE are shown in Fig. 2, A and B
. Each experimental group contained three perfused tumors and is designated according to the type of treatment. Perfusions were for 2 h. Tumor uptake of total plasma fatty acids and LA from the arterial blood perfusates among the seven groups were not significantly different, were comparable with those measured in vivo in Buffalo rats given free access to laboratory chow (5
, 15
, 17)
, and were unaffected by the different treatments. The rate of 13-HODE release into the venous blood in the control group accounted for about 2% of LA uptake. Perfusion for 2 h with arterial blood containing exogenous 13-HODE increased the rate of [3H]thymidine incorporation about 10 times and nearly doubled the DNA content of the control tumors, indicating that 13-HODE availability was limiting for tumor DNA synthesis. Perfusion with blood containing 13-KODE, a metabolite of 13-HODE that is released into the tumor venous blood at a rate about one-third of that of 13-HODE, was ineffective alone and did not increase the effectiveness of 13-HODE on either [3H]thymidine incorporation or DNA content. The increased availability of 13-HODE promoted tumor uptake of 13-HODE and about doubled (P < 0.001) the rate of release of 13-KODE (Fig. 2)
. NDGA treatment reduced the rate of [3H]thymidine incorporation and tumor DNA content to about one-third and one-half, respectively, of that observed in untreated tumors (Fig. 2, A and B)
. However the inhibitory effects of NDGA on tumor [3H]thymidine incorporation and DNA content were reversed by treatment with NDGA + 13-HODE during the 2-h perfusion. Tumor uptake of 13-HODE, which occurred in the presence of NDGA, reestablished the rate of [3H]thymidine incorporation and DNA content. 9-HODE, a metabolite of LA present in tumor venous blood in trace amounts (5)
, was ineffective in reversing the inhibitory effects of NDGA.
|
and [3H]thymidine incorporation (Fig. 3A)
and DNA contents (Fig. 3B)
. Because EFAD tumors contain only small amounts of LA and the LA concentration in EFAD donor blood is nearly undetectable (6)
, these data provide strong evidence for the direct mitogenic effect of 13-HODE.
|
shows that the rates of [3H]thymidine incorporation (19.5 ± 4.1 dpm/µg DNA) in untreated EFAD tumors (absence of endogenous LA) were identical to those observed in NDGA-treated tumors grown in rats fed an EFA-replete diet (21.2 ± 3.2 dpm/µg DNA; Fig. 2A
). Therefore, an inhibition of 13-HODE formation resulting either from an absence of LA in the arterial blood or from treatment of the tumor with a lipoxygenase inhibitor decreased [3H]thymidine incorporation to the same extent. LA was present during the 2 h of perfusion in the NDGA-treated tumors, but 13-HODE was not, indicating that 13-HODE not LA itself is required for tumor growth in vivo. |
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
and the dose-response curves shown in Fig. 3,A and B
, provide a biochemical explanation for the relationships among increased LA uptake, 13-HODE release into the tumor venous blood (5)
, [3H] thymidine incorporation and DNA content during perfusion in situ (6)
, and increased growth of hepatoma 7288CTC in vivo (5)
. The time required for the response in [3H]thymidine incorporation to exogenous 13-HODE was surprisingly brief; both NDGA-treated and LA-deficient tumors showed a robust increase in the rate of [3H]thymidine incorporation following a 2-h perfusion with 13-HODE. This fast response time is in good agreement with earlier data showing that perfused tumors exposed to a new, higher steady-state concentration of LA in arterial blood shifted to a new faster rate of [3H]thymidine incorporation after about 3 h of perfusion (12)
. Similarly, perfused tumors exposed to a new, but lower steady-state arterial blood LA concentration required about 3 h of perfusion before the new, slower rate of [3H] thymidine incorporation was established. These 3-h periods included time for changes in LA availability, lipoxygenase activity, and intracellular 13-HODE concentrations. Half-times for activation (or deactivation) of 1–1.5 h for DNA synthesis in a solid tumor in vivo are short and undoubtedly explain why increases in [3H]thymidine incorporation and DNA content were discernible in vivo a few hours after the plasma lipid concentrations were increased by an acute fast (17)
or induction of acute streptozotocin-induced diabetes (18)
. Considering the complex steps, many of which are unknown, between LA uptake at the cell membrane, 13-HODE production in the cytoplasm, and DNA synthesis in the nucleus, the pathway for LA-dependent growth in hepatoma 7288CTC (and presumably for LA-dependent growth in other rodent and human tumors) is highly efficient, developed, and controlled (see Ref. 19
).
Several recent in vitro studies have shown that lipoxygenase-derived metabolites of LA are important lipid mediators in signaling pathways for cell proliferation. Glasgow and Eling (20)
and Cowlen and Eling (21)
have reported that 13-HODE is a potent stimulator of EGF-dependent mitogenesis in BALB/c 3T3 fibroblasts (20)
and Syrian hamster embryo fibroblasts (21)
. EGF also stimulated the metabolism of LA to 13-HODE in these cell lines. The active LA metabolites formed by lipoxygenase activity in syrian hamster embryo fibroblasts were identified as the (S) enantiomers of 13-HPODE and 13-HODE (22)
. The (13R)-enantiomers were inactive, as were the arachidonate metabolites, (15S)-hydroperoxyeicosatetraenoic acid, and (15S)-HETE (22)
. Lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and NDGA effectively blocked mitogenesis and the conversion of LA to (13S)-HPODE and (13S)-HODE (20
, 21)
. Reddy et al. (23)
reported that [3H] thymidine incorporation in human breast carcinoma BT-20 cells in culture was increased by either transforming growth factor
or EGF. Both of these growth factors increased production of 13-HODE from added LA, and NDGA blocked 13-HODE formation and [3H]thymidine incorporation. Arachidonic acid metabolites of prostaglandin H synthetase were formed in low amounts; 13-HODE formation was not affected by the addition of indomethacin. The effect of 13-HODE on [3H]thymidine incorporation in BT-20 cells in the presence of NDGA was not described (23)
. In a recent study, Glasgow et al. (24)
showed that (13S)-HPODE and (13S)-HODE increased EGF-dependent mitogenesis and up-regulated EGF-dependent tyrosine phosphorylation by inhibiting the dephosphorylation of EGF receptor.
As judged from comparisons of results from the fibroblast and human BT-20 cell lines used in the in vitro experiments described above and results shown in Figs. 1
2
3
, it seems possible that 13-HODE production in hepatoma 7288CTC serves to augment EGF-dependent mitogenesis. EGF receptor is frequently overexpressed in animal and human neoplastic cells (25)
, and EGF stimulated DNA synthesis in primary cultures of human and rat hepatocytes (26)
and in two human hepatoma cell lines (27)
. However, 13(S)-HODE has also been reported to have additional activities. The activation of protein kinase C- mediated by 12(S)-HETE in murine B16 amelanotic melanoma cells (28)
and activation of protein kinase C in mouse epidermis (29)
are inhibited by (13S)-HODE. Both 9- and 13-HODE were identified as components of oxidized low-density lipoprotein in young and advanced human atherosclerotic lesions (30)
and were shown recently to be endogenous activators and ligands for peroxisome proliferator-activated receptor-
in macrophage foam cells (31)
.
A research goal of this laboratory is to understand the mechanisms through which hormonal, nutritional, and environmental factors control LA-dependent tumor growth. We believe that experiments performed with solid rodent and human (grown in immunodeficient rodents) tumors in vivo or during perfusion in situ will provide biochemical and physiological insights that cannot be duplicated in vitro. Recently, we demonstrated that exposure of tumor-bearing rats to constant light or to low levels of light contamination during the normal dark portion of the photoperiod caused a significant increase in the growth rate of hepatoma 7288CTC (32) . Increased light exposure during the dark phase decreased secretion of the pineal hormone melatonin, which is suppressed by light, and increased the tumor growth rates. The decreased plasma melatonin levels were associated with an increased fatty acid uptake and 13-HODE formation by hepatoma 7288CTC (32) . In the companion paper to this study (19) , we show that melatonin inhibition of fatty acid uptake in hepatoma 7288CTC in vivo and during perfusion in situ occurs via a melatonin receptor-mediated, Gi protein-linked inhibition of fatty acid transport. The decreased uptake of LA abolished 13-HODE formation and, therefore, the mitogenic signal for tumor DNA synthesis and growth described here. The addition of pertussis toxin, forskolin or cAMP analogues to the perfusate restored fatty acid transport, 13-HODE formation, and [3H]thymidine incorporation. Thus, tumor growth that is dependent on LA is regulated by both dietary LA intake and an environmental factor, light, through the neurohormone melatonin.
|
FOOTNOTES |
|---|
1 Supported by The Stephen C. Clark Research Fund of The Mary Imogene Bassett Hospital and by NIH United States Public Health Service Grant RO1-CA71697 (to D.E.B.). B.J.A. and S.S. are recipients of New York Academy of Science Summer Research Internships. 
2 These authors contributed equally to this research.
3 To whom requests for reprints should be addressed, at Bassett Research Institute, One Atwell Road, Cooperstown, NY 13326. Phone: (607) 547-3677; E-mail: dblask{at}usa.net
4 The abbreviations used are: LA, linoleic acid; HODE, hydroxyoctadecadienoic acid; KODE, ketooctadecadienoic acid; HPODE, hydroperoxyoctadecadienoic acid; HETE, hydroxyeicosatetraenoic acid; EFA, essential fatty acid; EFAD, EFA-deficient; NDGA, nordihydroguaiaretic acid; PGB2, 15-hydroxy-9-oxoprostatrienoic acid; HPLC, high-performance liquid chromatography; EGF, epidermal growth factor.
Received 4/13/99. Accepted 7/22/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-6 and -3 fatty acids on [3H]thymidine incorporation in hepatoma 7288CTC perfused in situ.. Br. J. Cancer, 66: 297-303, 1992.[Medline]
/EGF. Biochem. Biophys. Res. Commun., 231: 111-116, 1997.[Medline]
in melanoma cells: role of receptor-mediated hydrolysis of inositol phospholipids. Proc. Natl. Acad. Sci. USA, 92: 9323-9327, 1995.. Cell, 93: 229-240, 1998.[Medline]
This article has been cited by other articles:
|
|
 |
|
  V. Srinivasan, D W. Spence, S. R. Pandi-Perumal, I. Trakht, and D. P. Cardinali Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms Integr Cancer Ther, September 1, 2008; 7(3): 189 - 203. [Abstract] [PDF]
|
|
|
|
 |
|
 L. A. Sauer, R. T. Dauchy, D. E. Blask, J. A. Krause, L. K. Davidson, and E. M. Dauchy Eicosapentaenoic Acid Suppresses Cell Proliferation in MCF-7 Human Breast Cancer Xenografts in Nude Rats via a Pertussis Toxin-Sensitive Signal Transduction Pathway J. Nutr., September 1, 2005; 135(9): 2124 - 2129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Sauer, R. T. Dauchy, D. E. Blask, J. A. Krause, L. K. Davidson, E. M. Dauchy, K. J. Welham, and K. Coupland Conjugated Linoleic Acid Isomers and Trans Fatty Acids Inhibit Fatty Acid Transport in Hepatoma 7288CTC and Inguinal Fat Pads in Buffalo Rats J. Nutr., August 1, 2004; 134(8): 1989 - 1997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Blask, R. T. Dauchy, L. A. Sauer, and J. A. Krause Melatonin uptake and growth prevention in rat hepatoma 7288CTC in response to dietary melatonin: melatonin receptor-mediated inhibition of tumor linoleic acid metabolism to the growth signaling molecule 13-hydroxyoctadecadienoic acid and the potential role of phytomelatonin Carcinogenesis, June 1, 2004; 25(6): 951 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Bull, K. R. Steffensen, J. Leers, and J. J. Rafter Activation of PPAR {gamma} in colon tumor cell lines by oxidized metabolites of linoleic acid, endogenous ligands for PPAR {gamma} Carcinogenesis, November 1, 2003; 24(11): 1717 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Turgeon, S. Chouinard, P. Belanger, S. Picard, J.-F. Labbe, P. Borgeat, and A. Belanger Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases J. Lipid Res., June 1, 2003; 44(6): 1182 - 1191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. P.Kelavkar, C. Cohen, H. Kamitani, T. E.Eling, and K. F.Badr Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging Carcinogenesis, October 1, 2000; 21(10): 1777 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Sauer, R. T. Dauchy, and D. E. Blask Mechanism for the Antitumor and Anticachectic Effects of n-3 Fatty Acids Cancer Res., September 1, 2000; 60(18): 5289 - 5295. [Abstract] [Full Text]
|
|
|
|
|
|
D. E. Blask, L. A. Sauer, R. T. Dauchy, E. W. Holowachuk, M. S. Ruhoff, and H. S. Kopff Melatonin Inhibition of Cancer Growth in Vivo Involves Suppression of Tumor Fatty Acid Metabolism via Melatonin Receptor-mediated Signal Transduction Events Cancer Res., September 1, 1999; 59(18): 4693 - 4701. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
, 13 13-HODE and 13-KODE release, 30.7 ± 1.9 and 6.7 ± 2.7 ng/min/g;
, 13-HODE supply and uptake (0.54 ± 0.07 and 0.29 ± 0.06 µg/min/g) and 13-KODE release (11.9 ± 2.0 ng/min/g);
, 13-KODE supply (142.9 ± 20 ng/min/g), no 13-KODE uptake, 13-HODE release (41.5 ± 3.1 ng/min/g);
, 13-HODE supply and uptake (0.48 ± 0.06 and 0.25 ± 0.05 µg/min/g, respectively) 13-KODE supply and uptake (143.0 ± 12.0 ng/min/g), no 13-KODE uptake;
, no 13-HODE or 13-KODE release; 
, 13-HODE supply and uptake, (0.55 ± 0.05 and 0.29 ± 0.04 µ g/min/g), 13-KODE release (11.9 ± 1.9 ng/min/g); 
, no 13-HODE or 13-KODE released, 9-HODE supply and uptake (0.48 ± 0.5 and 0.1 ± 0.05 µg/min/g). A, asterisks indicate statistical differences from control, 13-KODE, NDGA, and NDGA + 9-HODE (P < 0.001). B, bars with different asterisk designations are statistically different (P < 0.001).
), 0.45 ± 0.1 (
), 0.75 ± 0.1 (
) µg/min/g tumor. Each tumor removed about 60% of the 13-HODE supplied. 13-KODE release was not determined. Values for each group in A and B are statistically different (P < 0.001) from the values of each other group.