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Biomedical subjects

J M Connolly

Publications and source records attributed to J M Connolly.

At least 19 recordsLinked to original sources
PubMed2004

Localized gene delivery using antibody tethered adenovirus from polyurethane heart valve cusps and intra-aortic implants.

The present study investigated a novel approach for gene therapy of heart valve disease and vascular disorders. We formulated and characterized implantable polyurethane films that could also function as gene delivery systems through the surface attachment of replication defective adenoviruses using an anti-adenovirus antibody tethering mechanism. Our hypothesis was that we could achieve site-specific gene delivery to cells interacting with these polyurethane implants, and thereby demonstrate the potential for intravascular devices that could also function as gene delivery platforms for therapeutic vectors. Previous research by our group has demonstrated that polyurethane elastomers can be derivatized post-polymerization through a series of chemical reactions activating the hard segment amide groups with alkyl bromine residues, which can enable a wide variety of subsequent chemical modifications. Furthermore, prior research by our group investigating gene delivery intravascular stents has shown that collagen-coated balloon expandable stents can be configured with anti-adenovirus antibodies via thiol-based chemistry, and can then tether adenoviral vectors at doses that lead to high levels of localized arterial neointima expression, but with virtually no distal spread of vector. Thus, we sought to create two-device configurations for our investigations building on this previous research. (1) Polyurethane films coated with Type I collagen were thiol activated to permit covalent attachment of anti-adenovirus antibodies to enable gene delivery via vector tethering. (2) We also formulated polyurethane films with direct covalent attachment of anti-adenovirus antibodies to polyurethane hard segments derivatized with alkyl-thiol groups, thereby also enabling tethering of replication-defective adenoviruses. Both formulations demonstrated highly localized and efficient transduction in cell culture studies with rat arterial smooth muscle cells. In vivo experiments with collagen-coated polyurethane films investigated an abdominal aorta implant model in pigs using a button configuration that simulated the blood contacting environment of a vascular graft. One week explants of the collagen-coated polyurethane films demonstrated 14.3+/-2.5% of neointimal cells on the surface of the implant transduced with green fluorescent protein - adenovirus (AdGFP) vector loadings of 1 x 10(8) PFU. PCR studies demonstrated no detectable vector DNA in blood or distal organs. Similarly, polyurethane films with direct attachment of antivector antibodies to the surface were used in sheep pulmonary valve leaflet replacement studies, simulating the blood contacting environment of a prosthetic heart valve cusp. Polyurethane films with antibody tethered AdGFP vector (10(8) PFU) demonstrated 25.1+/-5.7% of attached cells transduced in these 1 week studies, with no detectable vector DNA in blood or distal organs. In vivo GFP expression was confirmed with immunohistochemistry. It is concluded that site-specific intravascular delivery of adenoviral vectors for gene therapy can be achieved with polyurethane implants utilizing the antivector antibody tethering mechanism.

Adenoviridae↗
PubMed2003

DNA delivery from an intravascular stent with a denatured collagen-polylactic-polyglycolic acid-controlled release coating: mechanisms of enhanced transfection.

We previously demonstrated that DNA-polylactic-polyglycolic acid (PLGA)-coated stents can deliver genes to the arterial wall with reporter expression involving 1% of neointimal cells. The present study investigated a novel formulation utilizing denatured collagen in DNA-stent coatings; denatured collagen was hypothesized to enhance gene transfer due to adhesion molecule interactions and actin-related mechanisms. Arterial smooth muscle cells (SMCs) cultivated on denatured collagen had significantly greater plasmid DNA (beta-galactosidase) transfection than SMC grown on native collagen (18.3+/-1.2 vs 1.0+/-0.1%, P<0.001). The denatured-collagen effect was completely blocked with anti-alpha(v)beta(3) integrin antibody. SMCs cultivated on native collagen supplemented with tenascin-C (TN-C), a protein recognized by alpha(v)beta(3) integrins, showed a 33-fold increase in transfection compared to control (P<0.001); this effect was also blocked with anti-alpha(v)beta(3) antibody. We observed that cells grown on denatured collagen had marked F-actin-enriched stress fibers and intense perinuclear G actin, compared to those grown on native collagen, which demonstrated F-actin-enriched focal adhesions without perinuclear G-actin localization. Cytochalasin-D, an F actin depolymerizing agent, caused significantly increased SMC transfection in cells cultivated on native collagen compared to control cells (18.0+/-1.8 vs 3.02+/-0.9%, P<0.001) further supporting the view that actin-related cytoskeletal changes influence transfection. A denatured-collagen-PLGA composite vascular stent coating similarly resulted in increased plasmid DNA green fluorescent protein (GFP) expression compared to controls (P<0.001) in SMC cultures; the increased transfection was blocked by anti-alpha(v)beta(3) antibody. Pig coronary studies comparing denatured-collagen-PLGA-coated stents containing plasmid DNA (encoding GFP) to coated stents without DNA demonstrated 10.8% of neointimal cells transfected; this level of expression was almost an order of magnitude greater than previously reported with a DNA delivery stent. It is concluded that denatured collagen incorporated into plasmid DNA-stent coating formulations may increase the level of gene expression in vitro and in vivo because of integrin-related mechanisms and associated changes in the arterial smooth muscle cell actin cytoskeleton.

Actins↗
PubMed2001

Peptide length variants p2Ca and QL9 present distinct conformations to L(d)-specific T cells.

Recent advances have provided insights into how the TCR interacts with MHC/peptide complexes and a rationale to predict optimal epitopes for MHC binding and T cell recognition. For example, peptides of nine residues are predicted to be optimal for binding to H2-L(d), although 8 mer epitopes have also been identified. It has been predicted that 8 mer and 9 mer length variant peptides bound to L(d) present identical epitopes to T cells. However, in contrast to this prediction, we demonstrate here that the 8 mer peptide p2Ca and its 9 mer length variant QL9, extended by an N-terminal glutamine, assume distinct conformations when bound to L(d). We generated self-L(d)-restricted CTL clones specific for p2Ca that recognize L(d)/QL9 poorly if at all. This result is in sharp contrast to what has been observed with L(d)-alloreactive T cells that possess a much higher affinity for L(d)/QL9 than for L(d)/p2Ca. Alanine substitutions of the N-terminal residues of the QL9 peptide rescue detection by these self-L(d)/p2Ca-specific T cells, but decrease recognition by the L(d)-alloreactive 2C T cell clone. In addition, 2C T cell recognition of the p2Ca peptide is affected by different alanine substitutions compared with 2C T cell recognition of the QL9 peptide. These data clearly demonstrate that the p2Ca and QL9 peptides assume distinct conformations when bound to L(d) and, furthermore, demonstrate that there is flexibility in peptide binding within the MHC class I cleft.

Animals↗
PubMed2001

Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: a result of transformation or differentiation?

As with most cancers, the aetiology of human cutaneous melanoma is likely to be multifactorial and to include the accumulation of irreversible alterations in an unknown number of genes. Elucidating this molecular progression necessitates both the identification of genetic perturbations at each clinically relevant stage, and the assessment of their impact on the normal melanocyte. The observation that the epidermal melanocyte, in contrast to metastatic melanoma cells, requires activation of the protein kinase C (PKC) pathway to facilitate growth in vitro indicates that one or more isoforms (or substrates) of this large and complex family of proteins are among those that undergo alteration during the development of malignant melanoma. Consequently, a number of studies have investigated the expression of various PKC family members in both melanocyte and melanoma cell lines, without a consensus of opinion as to which isoforms are of biological significance in melanoma development and progression. The present study involved a comprehensive evaluation of the PKC profile in normal melanocytes and in 16 metastatic melanoma cell lines. The results show that the major difference in isoform expression between epidermal melanocytes and melanoma cells is the loss of PKCbeta protein expression in 90% of melanoma cell lines. Examination of PKCbeta in benign and malignant melanocytic lesions revealed that this protein is either downregulated or absent in both naevi and metastatic melanomas. We conjecture that, although the loss of PKCbeta expression is a common phenomenon in malignant melanocytes, it may be related more to a normal process of melanocytic differentiation than to malignant transformation.

Blotting, Western↗
PubMed2000

Kb, Kd, and Ld molecules share common tapasin dependencies as determined using a novel epitope tag.

The endoplasmic reticulum protein tapasin is considered to be a class I-dedicated chaperone because it facilitates peptide loading by proposed mechanisms such as peptide editing, endoplasmic reticulum retention of nonpeptide-bound molecules, and/or localizing class I near the peptide source. Nonetheless, the primary functions of tapasin remain controversial as do the relative dependencies of different class I molecules on tapasin for optimal peptide loading and surface expression. Tapasin dependencies have been addressed in previous studies by transfecting different class I alleles into tapasin-deficient LCL721.220 cells and then monitoring surface expression and Ag presentation to T cells. Indeed, by these criteria, class I alleles have disparate tapasin-dependencies. In this study, we report a novel and more direct method of comparing tapasin dependency by monitoring the ratio of folded vs open forms of the different mouse class I heavy chains, L(d), K(d), and K(b). Furthermore, we determine the amount of de novo heavy chain synthesis required to attain comparable expression in the presence vs absence of tapasin. Our findings show that tapasin dramatically improves peptide loading of all three of these mouse molecules.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Regulation of tumor angiogenesis by dietary fatty acids and eicosanoids.

Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular endothelial cell proliferation, migration, and capillary formation are stimulated by angiogenic growth factors, which include the proteins vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-beta, and eicosanoids synthesized from n-6 fatty acids. Clinical studies have shown that angiogenesis in solid tumors relates to a poor prognosis and, in premalignant lesions, indicates potential for cancerous transformation. High-fat, n-6 fatty acid-rich diets were associated with a relatively poor prognosis in breast cancer patients; in a nude mouse model the same diet enhanced breast cancer progression, whereas n-3 fatty acids exerted suppressive effects that were associated with impaired angiogenesis. Lipoxygenase and cyclooxygenase products of n-6 fatty acid metabolism are angiogenic in in vitro assays. This activity is blocked by pharmacological inhibitors of eicosanoid biosynthesis, and one, indomethacin, suppressed n-6 fatty acid-stimulated murine mammary carcinoma growth and metastasis and tumor vascularization. Review of the experimental data suggests that selective inhibitors of eicosanoid-synthesizing enzymes and dietary intervention with n-3 fatty acids merit clinical evaluation as adjuvant therapy and chemopreventive agents.

Angiogenesis Inhibitors↗
PubMed1999

Alloreactive and syngeneic CTL are comparably dependent on interaction with MHC class I alpha-helical residues.

The molecular basis for the difference in the strength of T cell responses to self vs alloantigens is unknown, but may reflect how T cells are selected in the thymus. Because T cells with a high affinity for foreign as opposed to self MHC molecules are able to mature, it has been proposed that alloreactive T cells may be more strongly dependent upon interaction with MHC residues than are self-restricted T cells. This study was undertaken to rigorously address this hypothesis. Whereas other studies have compared self vs alloantigen recognition of different MHC alleles by a single T cell clone, we have compared self vs alloantigen recognition of a single MHC allele, H-2Ld, by a large panel of self-restricted and alloreactive T cell clones. Target cells expressing Ld molecules mutated at several different potential TCR contact residues were analyzed to determine which residues are important for recognition by self-restricted vs alloreactive T cells. We unequivocally demonstrate that self-restricted and alloreactive T cells do not differ, but rather are comparably dependent on interaction with MHC residues. Importantly, both self-restricted and alloreactive T cells are dependent upon the same MHC residues as primary contacts and, in addition, share a common recognition pattern of Ld. Furthermore, our analysis enables us to provide a model for allotype-specific T cell recognition of Ld vs Kb class I molecules.

Amino Acid Substitution↗
PubMed1999

Omega-3 fatty acids as cancer chemopreventive agents.

There is both epidemiologic and experimental evidence that the long-chain omega-3 fatty acids (FAs), which occur at high levels in some fish oils, exert protective effects against some common cancers, notably those of breast, colon, and, perhaps, prostate. Multiple mechanisms are involved in this chemopreventive activity, including suppression of neoplastic transformation, cell growth inhibition and enhanced apoptosis, and antiangiogenicity; however, a common feature of most of these biological effects is the inhibition of eicosanoid production from omega-6 FA precursors. Several of the known risk factors for breast, and colon cancer may be favorably modified by dietary omega-3 FA supplementation, and the implementation of clinical chemoprevention trials is now feasible.

Animals↗
PubMed1999

Effects of reduced dietary linoleic acid intake, alone or combined with an algal source of docosahexaenoic acid, on MDA-MB-231 breast cancer cell growth and apoptosis in nude mice.

Diets rich in linoleic acid (LA), an n-6 fatty acid, stimulate the progression of human breast cancer cell solid tumors in athymic nude mice, whereas docosahexaenoic acid (DHA) and eicosapentaenoic acid, long-chain n-3 fatty acids, exert suppressive effects. In the present study we used a novel source of DHA, in triglyceride form, to determine the effects of feeding low levels of the fatty acid on the growth of MDA-MB-231 cells injected into the thoracic mammary fat pads of female nude mice. Four different isocaloric diets were used, all of which provided 20% (wt/wt) total fat. The control diets contained 8% (20 mice) or 4% (50 mice) LA; the n-3 fatty acid-supplemented groups of 50 mice were fed 4% LA-containing diets plus 2% or 4% DHA. The tumor growth rates were reduced significantly in mice fed the 4% LA compared with the 8% LA diet; the addition of 4% DHA to the 4% LA-containing diet produced a further reduction in tumor growth rate (p < or = 0.003 at and after Week 6). The final tumor weights were also reduced in the DHA-fed mice compared with the 8% LA dietary group (2% DHA, p = 0.02; 4% DHA, p = 0.01) and in the 4% DHA-fed mice compared with the 4% LA control group (p = 0.02); a similar trend for mice fed the lower level of DHA did not achieve statistical significance. Tumor prostaglandin E2 concentrations were reduced by feeding the lower LA level; further dose-dependent decreases occurred in the DHA dietary groups and were accompanied by reduced levels of 12- and 15-hydroxyeicosatetraenoic acids. These changes in eicosanoid biosynthesis may have been responsible for the observed decreases in cell proliferation, indicated by suppressed Ki-67 expression, and increases in apoptotic activity, as reflected in TdT-mediated dUTP nick end labeling immunohistochemical staining.

Animals↗
PubMed1999

Antiangiogenicity of docosahexaenoic acid and its role in the suppression of breast cancer cell growth in nude mice.

The addition of the omega-3 fatty acid (n-3 FA) docosahexaenoic acid (DHA), 4%, to a 20% (wt/wt) fat diet containing 4% linoleic acid (LA, n-6 FA) partially suppressed the growth of the MDA-MB-231 human breast cancer cell line as solid tumors in athymic nude mice. This reduced tumor growth was associated with significant inhibition of cell proliferation, as indicated by diminished Ki-67 nuclear proliferation marker expression, and an increase in TUNEL positive (apoptotic) cells (both p<0.001). The microvessel counts were also reduced in tumors from the DHA-supplemented dietary group of mice (p<0.001), and this suppression of angiogenesis was positively correlated with loss of Ki-67 expression. Tumor vascular endothelial cell growth factor (VEGF) concentrations were not reduced in the DHA-fed mice. It is postulated that the antiangiogenicity of DHA in this breast cancer model is related to our demonstrated inhibition of LA-derived prostaglandin E2, 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-HETE synthesis, reducing the paracrine stimulation by these known angiogenic eicosanoids on microvessel endothelial cells.

Angiogenesis Inhibitors↗
PubMed1998

Enhanced angiogenesis and growth of 12-lipoxygenase gene-transfected MCF-7 human breast cancer cells in athymic nude mice.

Transfection of the estrogen-dependent and poorly invasive MCF-7 human breast cancer cell line so that it stably overexpressed 12-lipoxygenase and secreted high levels of 12-hydroxyeicosatetraenoic acid when cultured with arachidonate resulted in rapid growth in athymic nude mice when compared with the parental line. This enhanced acquisition of tumor mass was a result of both increased cell proliferation and reduced apoptotic cell death and was accompanied by high angiogenic activity.

Animals↗
PubMed1998

Angiogenesis in two human prostate cancer cell lines with differing metastatic potential when growing as solid tumors in nude mice.

PURPOSE: Angiogenesis, typically a feature of aggressive tumors, is frequently associated with increased vascular endothelial growth factor (VEGF) production. Here, angiogenesis and angiogenic growth factor expression were assessed in two human prostate cancer cell models with differing metastatic potential. METHOD: Prostatic tumors were obtained by injecting either highly metastatic PC-3M cells or poorly metastatic DU145 cells into the surgically exposed prostate glands of nude mice. Angiogenesis was evaluated by immunohistochemical staining, and tumor VEGF, transforming growth factors-beta (TGF-beta1 and TGF-beta2), and basic fibroblast growth factor (bFGF) levels were determined by immunoassays (ELISAs). VEGF isoforms were detected by Western blotting in both solid tumor extracts, and in culture medium conditioned by the same cell lines (CM). RESULTS: Angiogenesis was much more evident in PC-3M tumors (vessel counts: PC-3M tumors 360 +/- 42, DU145 tumors 156 +/- 25; p = 0.003), but ELISA-determined VEGF levels were approximately 3-fold higher in both DU145 cell tumors, and in DU145 cell CM. However, Western blotting showed that PC-3M tumors, but not CM, contained VEGF isoforms with molecular weights of 43 and 57 kDa. TGF-beta2, but not TGF-beta1 concentrations were higher in DU145 cell tumors (p < 0.001); bFGF levels were higher in the PC-3M cell tumors (p < 0.05). CONCLUSIONS: When growing in nude mouse prostate glands, the PC-3M cell line provides a model for the angiogenic activity associated with aggressive prostate cancer. This is accompanied by the expression of immunoreactive VEGF which is not detected by an ELISA antibody raised against the conventional VEGF165, but appears on Western blots as what may prove to be novel high molecular weight species. Observed differences in TGF-beta1 and -beta2, and bFGF expression, may also be associated with an angiogenic phenotype.

Angiogenesis Inducing Agents↗
PubMed1998

Protein kinase C and its isoforms in human breast cancer cells: relationship to the invasive phenotype.

Total protein kinase C (PKC) activity and the expression of 9 isoforms were determined in the estrogen receptor (ER) positive MCF-7 human breast cancer cell line, this line transfected to overexpress either PKC-á or erbB2, and in 3 ER negative breast cancer cell lines. Relationships were sought between PKC and the expression of E-cadherin, alpha-catenin, and vimentin, and urokinase-type plasminogen activator (uPA). In general, PKC enzymic activity and the conventional isoforms PKC-alpha and -gamma were higher in the ER negative, compared with the ER positive, cell lines. Over-expression of PKC-alpha by MCF-7 cells, with ER loss, was associated with the emergence of PKC- expression and a relatively high level of PKC-gamma, features typical of cells with increased proliferation rates; there was also a loss of PKC-delta, consistent with acquisition of the metastatic phenotype. Transfection to overexpress erbB2, with ER retention and slowed growth, produced a decrease in PKC-alpha and -gamma. Vimentin was expressed by the ER negative MDA-MB-231, MDA-MB-435 and PKC-alpha-transfected MCF-7 cells; they also showed loss of E-cadherin and, apart from MDA-MB-435 cells, high levels of uPA secretion. The ER negative SKBr-3 cell line was exceptional in that it had relatively low total PKC activity, low PKC-alpha and -gamma expression and no emergence of vimentin despite loss of E-cadherin expression. Compared with the other two ER negative cell lines, both the SKBr-3 and MDA-MB-435 cells had low PKC activity and uPA secretion. These results are consistent with the involvement of PKC, and notably the conventional isoforms, in the development of the metastatic phenotype, and specifically with the loss of E-cadherin and acquisition of vimentin expression, and the enhanced production of uPA.

Blotting, Western↗
PubMed1998

Influence of dietary linoleic acid on experimental human breast cancer cell metastasis in athymic nude mice.

The effects of linoleic acid (LA), an omega-6 fatty acid precursor for prostaglandin biosynthesis, on the later stages of human breast cancer cell metastasis were studied by the intravenous injection of tumor cells into nude mice ( ). MDA-MB-435 cells were grown as solid tumors in donor mice fed a 12% or 2% LA-containing diet. These cells were harvested, and injected via a tail vein into recipient mice also fed a 12% LA (Group 1) or 2% LA (Group 2) diet. Other groups were fed 12% LA (Group 3) or 2% LA (Group 4), but injected with the cells grown in vitro in a low-LA culture medium. At necropsy 8 weeks later, the incidence of metastatic lung nodules was higher in Group 1 high LA donor/high LA recipient mice (p<0.001), and, to a lesser degree, Group 2 low LA donor/low LA recipient mice (p<0.05) compared with Groups 3 or 4. The extent of metastasis was significantly higher in Group 1 compared with any of the other groups, including metastasis to the ovaries, which occurred in 27% of the Group 1 mice. These findings show that LA, most likely by increased synthesis of cyclooxygenase products, stimulates metastasis, at least in part, by direct effects on the tumor cells, rather than on potential metastatic sites in the host.

Animals↗
PubMed1997

Effects of diet supplementation with wheat bran on serum estrogen levels in the follicular and luteal phases of the menstrual cycle.

There is both epidemiologic and experimental support for the hypothesis that a high-fiber diet can reduce breast cancer risk; this may be due, at least in part, to a reduction in circulating estrogens. This study examined the effects of three levels of wheat bran supplementation (5, 10, and 20 g/d for 2 mo) on the major serum estrogens during both the luteal and follicular phases of the menstrual cycle. The 10- and 20-g supplements, which increased the total dietary fiber intakes to approximately 20 and 32 g/d, respectively, resulted in significant decreases in the luteal serum estrone (P < 0.05 and < 0.02, respectively). The serum estradiol was significantly reduced in the 10-g wheat bran group after 2 mo (P < 0.05); the 20-g supplemented group showed a significant decrease in estradiol at 1 mo (P < 0.02), but not at 2 mo. No changes occurred in the estrone sulfate concentrations. During the follicular phase, the 10-g wheat bran group exhibited a significant reduction in the serum estrone (P < 0.02). Only the serum estrone sulfate showed any reduction with the 20-g supplement, and this just failed to achieve significance (P = 0.07). Serum sex hormone-binding globulin levels were unaffected by wheat bran. When of long duration, these effects may be sufficient to favorably influence breast cancer risk in Western women.

Adult↗
PubMed1997

Quantitation of the cell surface level of Ld resulting in positive versus negative selection of the 2C transgenic T cell receptor in vivo.

The 2C transgenic TCR is positively selected on Kb and is alloreactive for and negatively selected on Ld. To test an avidity model for positive selection, mice were bred to express different levels of surface Ld by varying the number of gene copies encoding beta 2-microglobulin (beta 2m) or Ld heavy chain. Whereas mice expressing 35% Ld (beta 2m+/- Ld+/-) negatively selected the 2C TCR, mice expressing 2% Ld (beta 2m-/- Ld+/-) positively selected the 2C TCR. Furthermore, 2C cytotoxic T lymphocytes selected on 2% Ld showed peptide-specific cytolytic activity against Ld/p2Ca targets. These findings provide clear in vivo evidence that positive selection can occur on very low levels of the same class I antigen capable of negative selection when expressed at higher levels.

Animals↗
PubMed1997

Effects of dietary menhaden oil, soy, and a cyclooxygenase inhibitor on human breast cancer cell growth and metastasis in nude mice.

The purpose of Study 1 was to examine the effect of dietary soy on the progression of MDA-MB-435 human breast cancer cell solid tumors in nude mice. When toasted soy chips were fed at levels of 5%, 10%, or 20% (wt/wt) in a high-fat, linoleic acid-rich diet for 12 weeks, there was a trend for larger mammary fat pad tumors to occur with increasing soy intake. However, compared with the controls the severity of macroscopic lung metastasis was reduced significantly in the groups fed 10% and 20% soy. Study 2 compared the effects of diets containing 23% corn oil (CO), 18% menhaden oil (MO) + 5% CO, 18% MO + 5% CO + 10% soy chips, and MO or soy-supplemented diets + indomethacin treatment in the same animal model. Feeding the 18% MO diet without soy or indomethacin reduced primary tumor growth; statistically significant effects were not observed in any of the other groups. All three of the groups with MO supplementation showed a reduction in the occurrence and severity of macroscopic lung metastases, together with the expected decreases in tumor prostaglandin E levels. These effects were most pronounced when MO was combined with indomethacin treatment. When indomethacin was given with dietary soy, the previously reported suppressive effect of the cyclooxygenase inhibitor on MDA-MB-435 cell tumor progression was lost, despite reductions in tumor prostaglandin E concentrations.

Animals↗