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J E Price

Publications and source records attributed to J E Price.

At least 19 recordsLinked to original sources
PubMed2001

DNA vaccination against neu reduces breast cancer incidence and metastasis in mice.

The gene for HER2/neu is overexpressed in 30-40% of breast and ovarian cancers, and this overexpression correlates with increased metastasis and poor prognosis. The HER2/neu gene product, a transmembrane protein kinase member of the EGF receptor family, has significant potential as a tumor antigen for vaccination. We inserted the sequence for neu into a novel plasmid called ELVIS containing a Sindbis virus replicon that reproduces multiple copies of mRNA. Mice vaccinated one time intramuscularly demonstrated a strong antibody response against A2L2, a murine breast cancer cell line transfected to express neu. Vaccinated mice challenged in the mammary fatpad with A2L2 had reduced tumor incidence and reduced tumor mass compared to mice challenged with tumor cells lacking the neu insert. Intradermal vaccination was also protective and required 80% less plasmid for a similar level of protection. Vaccination reduced the incidence of lung metastasis from mammary fatpad tumors and reduced the number of lung metastases resulting from intravenous injection of A2L2 cells. Cytotoxic T lymphocytes cultures of immune spleen cells with P815-neu cells produced high levels of interferon-gamma indicating an antigen-specific Th1-type immune response resulting from the vaccination. In a spontaneous breast tumor model using neu transgenic mice, vaccination with ELVIS-neu protected against development of spontaneous breast tumors. Our preclinical data indicate that therapeutic vaccination of patients with ELVIS-neu may reduce metastasis from HER2/neu-expressing breast and ovarian tumors.

Animals↗
PubMed2000

Adenoviral-mediated gene therapy with Ad5CMVp53 and Ad5CMVp21 in combination with standard therapies in human breast cancer cell lines.

Our objective was to determine the efficacy of adenoviral-mediated gene therapy with wild-type p53 or p21 in human breast cancer cells and investigate interactions with radiation and chemotherapy. Two human breast cancer cell lines, MDA-MB-231 and MDA-MB-435, both with p53 mutations, were transduced with adenoviral vectors containing wild-type p53 (Ad5CMV-p53) or p21/WAF1/Cip1 (Ad5CMV-p21), and the effects on growth were determined. Infection was combined with low-dose (1.4 - 3.7 Gy) irradiation to see if this would improve transduction efficiency and enhance numbers of cells killed. Transduction with either vector resulted in expression of p21WAF1/cip1 and growth inhibition, although Ad5CMV-p53 transduction produced greater growth inhibition than did Ad5CMV-p21. The cell lines differed in sensitivity to the vectors. The Ad5CMV-p53 vector in a multiplicity of infection (MOI) of 125 resulted in 50% to 80% inhibition of MDA-MB-231, while MOI 250 of the same vector resulted in 27% inhibition of MDA-MB-435. Infection with Ad5CMV-p21 produced modest growth inhibition in both cell lines (< or = 40% at MOI 200), although protein expression was detected at lower viral doses. Low dose gamma-irradiation (1.4 to 3.7 Gy) was used to try and improve the rate of gene transfer. Modest increases in transduction efficiency and duration of expression of a vector containing beta-galactosidase occurred in irradiated breast cancer cells. Radiation 24 hr before transduction with Ad5CMV-p53 increased the proportions of apoptotic MDA-MB-231 cells. The cells transduced with Ad5CMV-p21 were arrested in G1, yet when they were irradiated before adenoviral transduction, the overexpression of p21 protected the cells from the cytotoxic effects of the radiation. Clonogenic assays showed that Ad5CMV-p21 reduced the sensitivity of MDA-MB-231 to VP-16 and paclitaxel. Combining these drugs with Ad5CMV-p53 did not consistently or significantly decrease clonogenic survival.

Adenoviridae↗
PubMed1999

Increased levels of alpha6 integrins are associated with the metastatic phenotype of human breast cancer cells.

Integrins play an important role in interactions between cells and the extracellular matrix, and thus have a potential role in metastasis. Expression levels of alpha6, beta1 and beta4 integrin sub-units were measured in a panel of human breast cancer cell lines by RT/PCR, immunoprecipitation and flow cytometry. All the lines expressed alpha6, with the highest levels in the MDA-MB-231 and MDA-MB-435 cells. These grew the most aggressively and were metastastic in nude mice. Low levels of alpha6 protein were measured in breast cancer cells that were poorly tumorigenic and non-metastatic in nude mice, and there was an inverse relationship between ER and alpha6 expression. RT/PCR revealed that all lines expressed the 2 isoforms of alpha6, with the alpha6A isoform generally more abundant than alpha6B isoform. Clones of MDA-MB-435 were isolated by sterile sorting for cells with high or low alpha6 expression, and two variants established from metastases in nude mice were found to differ in alpha6 expression. When injected into nude mice. the alpha6-high variants produced significantly more lung metastases than the alpha6-low variants. beta1was abundant in all lines, while beta4 was not detected in MDA-MB- 134 cells, and in the MDA-MB-435 cells an alternately spliced variant of beta4 was identified. Sequencing of the alternate variant revealed a novel sequence from a splicing event in the cytoplasmic tail of beta4. None of the cells with this variant mRNA expressed detectable levels of beta4 protein. Our results suggest that high alpha6 expression in human breast cancer cells is associated with tumorigenicity and metastatic potential.

Animals↗
PubMed1999

Amplification of telomeric DNA directly correlates with metastatic potential of human and murine cancers of various histological origin.

Telomeres, repeated DNA sequences (T2AG3)n that guard the ends of chromosomes, serve as a checkpoint for cell-cycle progression and regulate cell senescence and apoptosis. Loss of the telomeric repeats promotes genomic instability, which is the hallmark of most cancer cells. Whether this loss differs among tumor cells with malignant potential is unknown and was the goal of this study. An all-human telomeric DNA probe was used to perform fluorescence in situ hybridization (FISH) and the telomeric signals in interphase nuclei were quantitated using a computer software package. Southern blot analysis was carried out to measure terminal restriction fragment length (TRFL) in multiple cancer cell lines, including nonmetastatic and metastatic human breast, lung, prostate, colon, brain, and renal carcinomas, as well as human and murine melanoma clones and somatic cell hybrids. The metastatic capability of all cell lines, clones and somatic cell hybrids was evaluated subsequent to orthotopic implantation into nude mice. FISH preparations with telomeric DNA probes showed that the mean percent telomeric area in the metastatic nuclei was significantly greater than their nonmetastatic counterparts and Southern blotting in selected samples confirmed our findings. These data suggest that amplification of telomeres is directly correlated with invasive and metastatic potential of murine or human tumor cells.

Animals↗
PubMed1999

Antitumor activity of poly(L-glutamic acid)-paclitaxel on syngeneic and xenografted tumors.

Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a new water-soluble paclitaxel derivative that has shown remarkable antitumor activity against both ovarian and breast tumors. The purpose of this study was to test whether the antitumor efficacy of PG-TXL depends on tumor type, as is the case for paclitaxel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL. We evaluated the therapeutic activity of PG-TXL against four syngeneic murine tumors (MCa-4, MCa-35, HCa-1, and FSa-II) inoculated i.m. into C3Hf/Kam mice, a human SKOV3ip1 ovarian tumor injected i.p. into nude mice, and a human MDA-MB-435Lung2 breast tumor grown in the mammary fat pad of nude mice. Two paclitaxel-responsive murine tumors, MCa-4 and MCa-35, showed significant growth delay with PG-TXL given as a single i.v. injection at its maximum tolerated dose of 160 mg of equivalent paclitaxel/kg or even at a lower dose of 120 mg of equivalent paclitaxel/kg. The other two murine tumors, HCa-1 and FSa-II, did not respond particularly well to either of the two agents, although significant growth delay was observed for both tumors with PG-TXL. In mice with SKOV3ip1 tumors, the median survival times for mice treated with PG alone and PG-TXL at doses of 60 or 120 mg of equivalent paclitaxel/kg were 43, 61, and 75 days, respectively; no survival difference was found between paclitaxel-treated and Cremophor vehicle-treated mice. In mice with MDA-MB-435Lung2 tumor, PG-TXL at a dose of 120 mg of equivalent paclitaxel/kg produced regression of the tumor in 50% of the animals, and in the remaining mice, micrometastases in the lung were found only in 25% of the animals. In comparison, treatment with paclitaxel at 60 mg/kg did not result in tumor regression, and the rate of lung metastases was 42%. These results clearly demonstrate that PG-TXL has significant therapeutic activity against breast and ovarian tumors tested in this study. Future studies to elucidate the mechanism of action of PG-TXL and to assess its clinical applications are warranted.

Animals↗
PubMed1998

Fas and Fas ligand interactions suppress melanoma lung metastasis.

Apoptosis induced by Fas (CD95) ligation is frequently lost during tumor progression; however, there is no direct evidence to support an association of Fas loss-of-function with metastatic tumor behavior. To determine whether Fas loss-of-function is critical for acquisition of the metastatic phenotype, we have compared the ability of Fas-sensitive K1735 murine melanomas to form spontaneous lung metastases in wild-type and Fas ligand-deficient mice. Fas-sensitive melanoma clones are highly tumorigenic but rarely metastatic in wild-type syngeneic mice. However, in Fas ligand-deficient mice, both the incidence and number of metastases are increased. These findings provide the first evidence that Fas-Fas ligand interactions can suppress metastasis and that tumor Fas loss-of-function may be causally linked to metastatic progression.

Animals↗
PubMed1998

Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein.

Over-expression of the epidermal growth factor receptor (EGFR) is a hallmark of numerous solid tumors, thus providing a means of selectively targeting therapeutic agents. Heparin-binding epidermal growth factor (HBEGF) binds to EGFRs with high affinity and to heparan sulfate proteoglycans, resulting in increased mitogenic potential compared to other EGF family members. We have investigated the feasibility of using HBEGF to selectively deliver a cytotoxic protein into EGFR-expressing tumor cells. Recombinant fusion proteins consisting of mature human HBEGF fused to the plant ribosome-inactivating protein saporin (SAP) were expressed in Escherichia coli. Purified HBEGF-SAP chimeras inhibited protein synthesis in a cell-free assay and competed with EGF for binding to receptors on intact cells. A construct with a 22-amino-acid flexible linker (L22) between the HBEGF and SAP moieties exhibited an affinity for the EGFR that was comparable to that of HBEGF. The sensitivity to HBEGF-L22-SAP was determined for a variety of human tumor cell lines, including the 60 cell lines comprising the National Cancer Institute Anticancer Drug Screen. HBEGF-L22-SAP was cytotoxic in vitro to a variety of EGFR-bearing cell lines and inhibited growth of EGFR-over-expressing human breast carcinoma cells in vivo. In contrast, the fusion protein had no effect on small-cell lung carcinoma cells, which are EGFR-deficient. Our results demonstrate that fusion proteins composed of HBEGF and SAP exhibit targeting specificity and cytotoxicity that may be of therapeutic value in treating a variety of EGFR-bearing malignancies.

Epidermal Growth Factor↗
PubMed1998

Overexpression of both p185c-erbB2 and p170mdr-1 renders breast cancer cells highly resistant to taxol.

We recently found that overexpression of p185c-erbB2 in c-erbB2 transfected MDA-MB-435 breast cancer cells (435.eB transfectants) confers a 5-9-fold increase in Taxol resistance. To examine whether Taxol resistance is a common phenomenon in other c-erbB2 overexpressing breast cancer cell lines, we tested a panel of human breast cancer cell lines established from different patients and expressing pl85c-erbB2 at different levels for their sensitivity to Taxol and Taxotere, a synthetic taxoid. Higher expression of p185c-erbB2 in these breast cancer cell lines indeed correlated well with resistance to Taxol and Taxotere, and the degree of resistance was about 100-fold that in c-erbB2-overexpressing 435.eB transfectants, demonstrating that these breast cancer cells are highly resistant to Taxol. Since mdr-1-encoded p-glycoprotein (p170mdr-1) has been implicated in Taxol resistance, we next examined the p170mdr-1 levels in these breast cancer cell lines that are highly resistant to Taxol. Higher levels of p170mdr-1 expression were found in several breast cancer cell lines that are highly resistant to Taxol. Since these same breast cancer cell lines also expressed higher levels of p185c-erbB2, we sought to determine the relative contribution of p185c-erbB2 and p170mdr-1 overexpression to Taxol resistance. We first specifically down-regulated cell surface p185c-erbB2 using anti-p185c-erbB2 monoclonal antibodies and assayed sensitivity of these cells to Taxol. We next specifically inactivated p170mdr-1 function using p170mdr-1 blockers (thioridazine or verapamil) and again assayed Taxol sensitivity. Both p185c-erbB2 down-regulation and p170mdr-1 blockade significantly sensitized the breast cancer cell lines to Taxol. The results indicate that overexpression of either p185c-erbB2 or p170mdr-1 renders human breast cancer cells resistant to Taxol. Furthermore, p185c-erbB2 synergizes with p170mdr-1 conferring higher degrees of Taxol resistance. Finally, combination therapy (down-regulation of p185c-erbB2 plus blocking p170mdr-1 plus administration of Taxol) may be beneficial to breast cancer patients whose tumors express high levels of both p185c-erbB2 and p170mdr-1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice.

BACKGROUND: By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice. METHODS: Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies. RESULTS: Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/ VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery. CONCLUSIONS: The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.

Animals↗
PubMed1998

Social marketing sexually transmitted disease and HIV prevention: a consumer-centered approach to achieving behaviour change.

This paper proposes that international sexually transmitted disease (STD)/HIV prevention efforts might be enhanced by the application of social marketing principles. It first outlines the conceptual basis of social marketing approaches to health behaviour change generally and then explores key issues and opportunities for using these principles to improve current STD/HIV prevention efforts.

Condoms↗
PubMed1997

Dominant-negative CREB inhibits tumor growth and metastasis of human melanoma cells.

The ATF/CREB family of eukaryotic transcription factors contain the bZIP structural motif and mediate their transcriptional activities via heterodimerization with ATF and AP-1 family members. Quenching of CREB-associated proteins by a dominant-negative CREB (KCREB) that is mutated within its DNA-binding domain decreases radiation resistance of human melanoma cells. The purpose of this study was to determine the role of CREB in tumor growth and metastasis of human melanoma using KCREB. Highly metastatic MeWo human melanoma cells were transfected with the KCREB expression vector and subsequently analysed for changes in their tumorigenic and metastatic potential. Expression of KCREB in MeWo human cells decreased their tumorigenic and metastatic potential in nude mice compared with parental and control transfected cells. The KCREB-transfected cells displayed downregulation of 72 kDa collagenase type IV (MMP-2) mRNA expression and activity and decreased invasiveness through Matrigel-coated filters. Moreover, transcriptional activities mediated by the CAT gene driven by the MMP-2 promoter were decreased by 14-45-fold in KCREB-transfected cells. In addition, the cell-surface adhesion molecule MCAM/MUC18 that is involved in metastasis of human melanoma was downregulated in the KCREB-transfected cells. These data indicate that, through their transcriptional activities, CREB and its associated proteins play an important role in the acquisition of the metastatic phenotype of human melanoma cells.

Animals↗
PubMed1997

Molecular profile of advanced-stage transitional cell carcinoma of the ovary.

OBJECTIVES: Our purpose was to determine the molecular profile of advanced-stage transitional cell carcinoma in terms of immunostaining for p53, epidermal growth factor receptor and HER-2/neu, deoxyribonucleic acid index, and S-phase fraction and to analyze the prognostic significance of these markers. STUDY DESIGN: Archival paraffin-embedded tissue blocks from 29 advanced stage transitional cell carcinomas were obtained. Selected sections of the primary tumors were immunostained for p53, epidermal growth factor receptor, and HER-2/neu; deoxyribonucleic acid ploidy and S-phase fraction were determined with use of flow cytometry. Clinical information was abstracted from the medical records. Survival times were analyzed according to the life-table methods of Kaplan and Meier, and the statistical significance of the various factors was tested with the log-rank test. The proportional hazards model of Cox was used to identify prognostic factors. RESULTS: Positive immunostaining was observed for p53 in 13 cases (45%), for epidermal growth factor receptor in 14 cases (50%), and for HER-2/neu in 19 cases (65%). Tumors were diploid in 16 cases (55%) and aneuploid in 13 (45%). The S-phase fraction was < or = 15% (mean) in 13 cases (45%) and > 15% in 16 cases (55%). The median survival for the entire group was 52 months. None of the above variables had a significant effect on survival time. CONCLUSION: Neither immunostaining for p53, epidermal growth factor receptor, and HER-2/neu nor deoxyribonucleic acid ploidy nor S-phase fraction allowed us to distinguish transitional cell carcinoma from other more common epithelial ovarian cancers. In addition, no prognostic significance was associated with these biomarkers. A study of larger numbers of cases may be more elucidative.

Adult↗
PubMed1997

Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells.

The occurrence of breast cancer metastases is preferential to certain organs. Astrocytes may play an important role in the development of brain metastases, as these cells have been shown to respond to extracellular stimuli by producing many cytokines and growth factors that can modulate tumor cell proliferation, growth, and/or metastases. To test this hypothesis, we analyzed the responses of the human breast cancer cell line MDA-MB-435 and its metastatic sublines to astrocyte primary cultures from newborn rat cerebra. Astrocyte purity of the glial cell cultures was demonstrated by glial fibrillary acidic protein and rat neural antigen-2 (Ran-2) immunopositive staining. The 435-Br1 cell line, which was derived from a brain metastases in a nude mouse, showed increased adhesion to astrocytes and enhanced growth in vitro in the presence of media from Con A-stimulated astrocytes, relative to the parental MDA-MB-435 and the lung metastasis-derived variant 435-Lung2. Furthermore, the growth-stimulatory effect was partially reversed by anti-IL-6, anti-transforming growth factor beta (anti-TGF beta), and anti-IGF-I antibodies, indicating that these metastatic cells use exogenous cytokines as paracrine growth factors. In an attempt to elucidate the role of several biologic-response modifiers produced by astrocytes, we tested the responses of MDA-MB-435 cells to purified cytokines and growth factors. We found that the addition of recombinant human or mouse IL-6 produced a variety of responses in the different 435 metastatic variants. Furthermore, IL-6 receptor (IL-6R) expression was slightly increased in the 435-Br1 cells, and exogenous IL-6 rescued 435-Br1 cells from apoptosis in serum-depleted cultures. No apoptotic protective effect was observed in either MDA-MB-435 parental cells or 435-Lung2 cells. Thus, responses to exogenous IL-6 might determine the differences among these metastatic variants by extending cell survival of selected subpopulations, giving them the opportunity to respond to growth factors or other favorable conditions that might be present. These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases by breast cancer cells.

Adult↗
PubMed1997

Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism.

The introduction of adenovirus 5 E1A into the SKOV3ip1 ovarian cancer cell line was shown previously to suppress HER2/neu expression and reduce the malignant potential of these cells (Yu et al., Cancer Res., 53: 891-898, 1993). In this report, we show that reduction of p185 in cells stably expressing E1A protein was coincident with increased sensitivity to cytotoxic agents. The LD50 of cisplatin was reduced 6-fold, and the LD50 of paclitaxel and doxorubicin was reduced 10-fold in E1A-expressing cells compared with control cells. The growth of SKOV3ip1 and control cells was unchanged in the presence of 150 ng/ml of tumor necrosis factor-alpha, whereas the growth of E1A-expressing cells was reduced by 30 to 40%. When we used a physiologically obtainable concentration of paclitaxel (0.5 microM), DNA laddering consistent with apoptotic cell death was seen after a 24-h exposure in the E1A-expressing cells, whereas laddering and DNA fragmentation were only detected in DNA from control cells after longer exposure (48 h) at a 20-fold higher concentration of paclitaxel. The SKOV3ip1 cells do not express p53 protein; hence, the induction of apoptosis by paclitaxel is through a p53-independent pathway. Despite their diverse mechanisms of action, the cytotoxic effects of cisplatin, doxorubicin, paclitaxel, and tumor necrosis factor-alpha were enhanced by the expression of E1A proteins in the SKOV3ip1 ovarian cancer cells. This suggests that these agents share a common final pathway of cell killing, which may represent a potential therapeutic target in resistant ovarian cancers.

Adenovirus E1A Proteins↗
PubMed1996

Inhibition of human breast cancer metastasis in nude mice by synthetic glycoamines.

We have examined the effect of synthetic low molecular weight glycoamine analogues on the metastasis of MDA-MB-435 human breast carcinoma xenografts growing in the mammary fat pads of nude mice. Initial in vitro screening of a panel of synthetic glycoamines was performed using a clonogenic growth assay in 0.9% agarose. Eight of nine compounds manifested a significant dose-dependent inhibition of colony formation by MDA-MB-435 cells in 0.9% agarose. The relative activity ranks of the compounds, based on ID50S independently determined for each synthetic glycoamine analogue, identified N-(1-deoxy-D-lactulos-1-yl)-L-leucine (Lac-L-Leu), N-(1-deoxy-D-fructos-1-yl)-D-leucine (Fru-D-Leu), N-(1-deoxy-D-fructos-1-yl)-L-phenylalanine, and N-(1-deoxy-D-fructos-1-yl)-L-leucine as the most effective inhibitors of colony formation. Two separate experimental treatment protocols were used to examine the effect of selected synthetic glycoamines on human breast cancer growth and metastasis in athymic nude mice. Group A mice were treated intraperitoneally daily from day 2 after injection of the breast cancer cells until the end of the experiment (17 weeks). In group B, the mice were untreated until the mean tumor diameter was 10 mm, at which time daily i.p. treatment began. After 7 days, the primary tumors were resected, and the mice were treated for an additional 4 weeks (a total of 5 weeks of treatment). The synthetic glycoamines did not have significant antitumor effects, and there was no difference in the tumor incidence or tumor growth rates in mice treated continuously with synthetic glycoamines or PBS. The significant antimetastatic activity of synthetic glycoamines was detected in both experimental treatment protocols. In mice continuously treated with synthetic glycoamines according to protocol A, the incidence of metastasis was decreased 4.6-fold (P = 0.014) and 2.7-fold (P = 0.031) in mice treated with Fru-D-Leu and Lac-L-Leu, respectively. In mice in protocol B, the incidence of pulmonary metastasis was decreased 1.9-fold (P = 0.069) and 2.5-fold (P = 0.042) in mice treated with Fru-D-Leu and Lac-L-Leu, respectively. Correspondingly, the average number of spontaneous pulmonary metastases was reduced from 37 in control mice to 0.2 (P = 0.005) and 0.9 (P < 0.02) in mice treated according to the protocol A with Fru-D-Leu and Lac-L-Leu, respectively. Treatment of mice with N-(1-deoxy-D-fructos-1-yl)-L-leucine did not have significant antimetastatic effects, and no reduction in metastasis incidence or number was noted in mice treated with this synthetic glycoamine analogue. The treated animals had no apparent toxicity from chronic daily injection (up to 17 weeks of treatment) of synthetic glycoamines, and no obvious pathology was noted in the histological slides of the livers, kidneys, or spleens of the treated mice. Therefore, we have identified two synthetic glycoamines (Fru-D-Leu and Lac-L-Leu) that were the effective inhibitors of spontaneous human breast cancer metastasis in nude mice. Potential mechanisms for antimetastatic activity of synthetic glycoamines may include the inhibition of beta-galectin-mediated homotypic cancer cell aggregation and induction of apoptosis in target cells.

Amino Acids↗
PubMed1996

Inhibition of colony formation in agarose of metastatic human breast carcinoma and melanoma cells by synthetic glycoamine analogs.

We studied the influence of 10 synthetic glycoamine analogs on colony formation in 0.3 and 0.9% agarose by metastatic human breast carcinoma (MDA-MB-435) and melanoma (TXM-13) cells. Nine synthetic analogs significantly inhibited the colony formation in 0.9% agarose of MDA-MB-435 human breast carcinoma cells; five compounds caused a 73-83% reduction of colony formation. Seven synthetic glycoamines caused a significant inhibition of colony formation in 0.9% agarose by TXM-13 melanoma cells with the inhibitory effect ranging from 71 to 87%. The 50% inhibition (I50) doses and relative activity rank of the compounds were similar for both breast carcinoma and melanoma cell lines. The murine B16 melanoma cell aggregation assay was employed to elucidate the potential mechanism(s) of the inhibitory activity of synthetic glycoamines. The relative activity ranks of the compounds based on the independently determined I50 doses for both cell aggregation and clonogenic growth assays were very similar for the four most active synthetic analogs and clearly indicated the importance of hydrophobic amino acid in mediating the bioactivity of synthetic glycoamines. In both experimental systems (clonogenic growth in agarose and cell aggregation assay) the leading compound was N-(1-deoxy-D-fructos-1-yl)-D-leucine (Fru-D-Leu) and the least active analog was N-(l-deoxy-D-fructos-1-yl)-glycine (Fru-Gly). These results show that synthetic glycoamines may act by competing for specific carbohydrate-lectin interactions, particularly those involving beta-galactoside-specific lectins expressed on metastatic cells.

Amino Sugars↗