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Biomedical subjects

R C Bast

Publications and source records attributed to R C Bast.

At least 91 records · Page 5Linked to original sources
PubMed1996

Breast cancer cells are effectively purged from peripheral blood progenitor cells with an immunomagnetic technique.

Peripheral blood progenitor cells (PBPCs) are being used increasingly to provide hematopoietic support after intensive chemotherapy. However, many investigators have detected tumor cells contaminating PBPC collections. Methods that eliminate the tumor cells and spare the normal hematopoietic progenitor cells may improve the number of long-term, disease-free survivors after intensive chemotherapy. We developed an effective method using anti-breast cancer murine monoclonal antibodies (MoAbs) and immunomagnetic beads to eliminate a low percentage of breast cancer cells from PBPCs. We identified optimal anti-breast cancer MoAbs that react with membrane glycoproteins and conditions for selective removal of tumor cells. Using three anti-breast cancer MoAbs (260F9, 317G5, and 520C9) at 0.8 microgram/ml, a cell concentration of 2 x 10(8) cells/ml and a bead:total cell ratio of 0.75 beads:1 cell, we eliminated 3.3-4.8 (mean, 4.1) logs of tumor cells consistently from a model system with 1% breast cancer cells and 99% normal PBPCs. Similar levels of tumor cell elimination were obtained with three breast cancer cell lines. Colony-forming units were not affected adversely, with a mean recovery of 200% compared with the control. A clinical trial has begun that uses immunomagnetically purged, autologous bone marrow and PBPCs to support patients with metastatic breast cancer receiving high-dose chemotherapy.

Antibodies, Monoclonal↗
PubMed1995

Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers.

Stored samples from women in the Stockholm screening study were reassayed for CA125II (Centocor, Malvern, PA) and OVX1. The postmenopausal women older than age 50 without ovarian cancer were randomly split into a training set to develop a screening test based on longitudinal marker levels and a second set to validate the test. The CA125II data from each woman is summarized by the slope and intercept from a linear regression of log(CA125II) on time since first sample. The slope versus the intercept for the training set and the ovarian cancer cases formed a bivariate scatter plot. A curve was drawn on the scatter plot that separated most of the women with ovarian cancer from all other women; it delineated a screening test. The specificity of this test was examined on the validation set with a specificity of 99.8%. Bayes' theorem was used to calculate the risk of ovarian cancer (ROC) based on the intercept, slope, and assay variability. It is important to account for assay variability because it can produce large slopes over short periods of time. The maximum risk, which identified 83% (5 of 6) of the ovarian cancers detected within a year of last assay, was applied as a test to the training set and confirmed a high specificity of 99.7%. With this specificity and sensitivity, the ROC algorithm using the CA125II assay has an estimated positive predictive value of 16%, substantially greater than the positive predictive value based on a single assay. Further study is planned to confirm the sensitivity of this approach.

Aged↗
PubMed1995

Ovarian cancer screening. The use of serial complementary tumor markers to improve sensitivity and specificity for early detection.

BACKGROUND: The use of serum tumor markers for the early detection of ovarian cancer has been limited because of their low sensitivity and low positive predictive value. CA 125 levels are elevated in only about one half of women with Stage I ovarian cancer, thus researchers have focused on using the serial measurement of complementary markers to improve the sensitivity, specificity, and positive predictive value of this approach for screening. METHODS: Multiple serum markers have been analyzed in women with early stage epithelial ovarian cancer. CA 125, CA 15-3, C19-9, CA 54-61, CA 72-4, CEA, HMFG2, IL-6, IL-10, LSA, M-CSF, NB70K, OVX1, PLAP, TAG72, TNF, TPA, and UGTF have been studied alone and in combination in this setting. Complementarity and logistic regression analyses have been performed to assess those markers with the highest likelihood of improving sensitivity and specificity for early detection. Serial analysis of a second-generation CA 125 measuring the intercept (initial level) and slope (change of levels over time) can be used to discriminate malignant cases from benign and normal cases. RESULTS: Analyses have shown that the serial measurement of the new, more sensitive CA 125 has a high sensitivity (83%), specificity (99.7%), and positive predictive value (16%) for the early detection of ovarian cancer. OVX1 used in combination with CA 125 provides the best complementarity. Serial measurements of the two markers have sensitivities in the range of that for transvaginal ultrasonography. CONCLUSION: The serial measurement of complementary serum markers can improve the use of marker screening for epithelial ovarian cancer. With the use of several different methods of analysis, it has been shown that this approach improves the sensitivity, specificity, and positive predictive value of serum markers CA 125 and OVX1. A procedure that measures complementary serum markers over time can be used as a primary screening technique followed by transvaginal ultrasonography. This could provide a cost-effective means of early detection and could significantly decrease the probability of surgical intervention for false-positive test results.

Biomarkers, Tumor↗
PubMed1995

Soluble interleukin-2 receptor alpha is elevated in sera of patients with benign ovarian neoplasms and epithelial ovarian cancer.

BACKGROUND: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential. METHODS: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay. RESULTS: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively. CONCLUSION: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.

Biomarkers, Tumor↗
PubMed1995

Regulation of apoptosis in normal and malignant ovarian epithelial cells by transforming growth factor beta.

Previously, we found that transforming growth factor beta (TGF-beta) inhibits proliferation of normal human ovarian epithelial cells. In addition, although only 1 of 5 immortalized ovarian cancer cell lines was inhibited, TGF-beta inhibited proliferation of 19 of 20 primary epithelial ovarian cancers. In this study, we examined whether TGF-beta induces apoptosis in normal and malignant ovarian epithelial cells. Among 5 immortalized cell lines, only OVCA 420 is markedly growth inhibited by TGF-beta, and this was the only cell line in which TGF-beta elicited DNA fragmentation characteristic of apoptosis. Induction of apoptosis in OVCA 420 was time and concentration dependent and could be partially inhibited by concurrent treatment with an anti-TGF-beta mAb. Although apoptosis was not seen in normal ovarian epithelial cells (n = 7), [3H]thymidine incorporation was inhibited in all cases [mean = 61.2 +/- 7.2% (SD) of untreated control; P < 0.01]. Similarly, TGF-beta inhibited [3H]thymidine incorporation in all 10 primary ovarian cancers (mean = 40.4 +/- 7.1% of control; P < 0.01), but only 3 of 10 (30%) were found to undergo apoptosis when treated with TGF-beta. There was no relationship between p53 status of the ovarian cancers and the ability of TGF-beta to elicit apoptosis. In conclusion, TGF-beta inhibits proliferation but does not induce apoptosis in normal human ovarian epithelial cells. In contrast, some ovarian cancers that are growth inhibited by TGF-beta also undergo apoptosis. These data are consistent with the hypothesis that malignant cells are more susceptible to apoptosis than their normal nontransformed counterparts.

Antibodies↗
PubMed1995

Molecular approaches to prevention and detection of epithelial ovarian cancer.

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.

Diagnosis, Differential↗
PubMed1995

Detection of tumor cells in the bone marrow of stage IV breast cancer patients receiving high-dose chemotherapy: the role of induction chemotherapy.

High-dose chemotherapy and hematopoietic support can produce long-term, disease-free remissions in selected patients with metastatic breast cancer. Occult bone marrow involvement may contribute to late relapse. We used five anti-breast cancer monoclonal antibodies and flow cytometry with cytological analysis of sorted immunostained cells to detect tumor cells in the bone marrow in two cohorts of patients. The first (Upfront) cohort was treated with a single course of high-dose chemotherapy and autologous bone marrow support (ABMS) without induction chemotherapy. The second (AFM) cohort received induction chemotherapy with doxorubicin, 5-fluorouracil and methotrexate prior to high-dose chemotherapy and ABMS. Of the 15 Upfront patients, seven (47%) had immunostained cells in the harvested bone marrow by flow cytometry and 8/15 (53%) had positive cytologies. Of the 49 AFM patients studied, nine (18%) had immunostained cells in the bone marrow, and only 1/49 (2%) had positive cytologies. Induction chemotherapy significantly decreased bone marrow contamination as detected by flow cytometry and cytology in patients with breast cancer. The detection of immunostained cells in the bone marrow did not predict for relapse or overall survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

The tyrosine kinase activity of the C-erbB-2 gene product (p185) is required for growth inhibition by anti-p185 antibodies but not for the cytotoxicity of an anti-p185-ricin-A chain immunotoxin.

Our previous studies have demonstrated that 7 of 10 IgG antibodies against distinct epitopes on the extracellular domain of the c-erbB-2 gene product (p185) inhibit the anchorage-independent growth of SKBr3 human breast-cancer cells that overexpress this transmembrane tyrosine kinase growth-factor receptor. Two of 7 growth-inhibitory antibodies also block the binding and function of the gp30 and p75 c-erbB-2 ligands. In this report we have studied phosphorylation of p185 and different intracellular substrates after binding of antibodies that do or do not inhibit tumor-cell growth. A correlation has been found between antibodies that inhibit growth and the intensity of tyrosine phosphorylation of p185. At late intervals, serine phosphorylation of at least 3 intracellular substrates is increased preferentially by growth-inhibitory antibodies. To test the importance of p185 kinase activity more critically, NIH3T3 cells were transfected with an expression vector containing the full-length human c-erbB-2 gene (cell line 17313), c-erbB-2 with deletion of the kinase region from codons 751-979 (cell line 9309) or c-erbB-2 with deletion of most of the intracellular domain from codons 684-1255 (cell line 9310). Unconjugated antibodies inhibited anchorage-independent growth of 17313 cells as well as SKBr3 cells, but did not inhibit growth of either 9309 or 9310 cells. In contrast, the cytotoxic effect of anti-p185-ricin A chain (RTA) conjugates was comparable for 17313, 9309 and 9310. The tyrosine-kinase activity of p185 is required for growth inhibition mediated by unconjugated anti-p185 antibodies, but not for the cytotoxic activity of anti-p185-RTA immunotoxins.

3T3 Cells↗
PubMed1994

Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory agent produced primarily by activated monocytes and macrophages. TNF-alpha is synthesized as a precursor protein of M(r) 26,000 (26K) which is processed to a secreted 17K mature form by cleavage of an Ala-Val bond between residues 76-77. The enzyme(s) responsible for processing pro-TNF-alpha has yet to be identified. Here, we describe the capacity of a metalloproteinase inhibitor, GI 129471, to block TNF-alpha secretion both in vitro and in vivo. The inhibition is specific to TNF-alpha; the production of other secreted cytokines, such as the interleukins IL-1 beta, IL-2, or IL-6, is not inhibited. The mechanism of inhibition occurs at a post-translational step in TNF-alpha production. Our data suggest that TNF-alpha processing is mediated by a unique Zn2+ endopeptidase which is inhibited by GI 129471 and would represent a novel target for therapeutic intervention in TNF-alpha associated pathologies.

Animals↗
PubMed1994

Transforming growth factor-beta inhibits proliferation of human ovarian cancer cells obtained from ascites.

BACKGROUND: Previously, the authors found that immortalized ovarian cancer cell lines generally were resistant to the growth inhibitory effect of transforming growth factor-beta and frequently had lost the ability to produce or activate this growth factor. In this study, the authors examined whether early passage epithelial ovarian cancer cells obtained from ascites are growth-inhibited by or produce transforming growth factor-beta. METHODS: Ovarian cancer cells were purified from ascites by percoll gradient density centrifugation, and inflammatory cells were removed using anti-CD45 antibody. The effect of transforming growth factor-beta on the proliferation of ovarian cancer cells was assessed using the thymidine incorporation assay. Immunohistochemical staining for transforming growth factor-beta 1 and beta 2 also was performed in these cells. RESULTS: Transforming growth factor-beta (10 ng/ml) significantly inhibited [3H]thymidine incorporation in 19 of 20 (95%) primary ovarian cancers (P < 0.05). In cases in which significant inhibition was seen, the mean thymidine incorporation was 33 plus or minus 28% of control values. In addition, there was no difference in dose-dependent inhibition of proliferation between ovarian cancer cells and normal ovarian epithelial cells. Eleven of 18 ovarian cancers (61%) were found to express immunohistochemically detectable transforming growth factor-beta, but immunostaining was not observed in 39% of cases. CONCLUSIONS: Although most primary ovarian cancer cells remain sensitive to the growth-inhibitory effect of transforming growth factor-beta, loss of production may interrupt the transforming growth factor-beta autocrine inhibitory loop and play a role in the development of some ovarian cancers.

Ascites↗
PubMed1994

Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support.

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

Adult↗
PubMed1994

Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer.

BACKGROUND: Several molecular-genetic alterations in endometrial cancers, including aneuploidy and aberrant expression of p53 and HER-2/neu, have been associated with poor prognosis. To determine the importance of molecular-genetic factors relative to more traditional surgical-pathologic prognostic factors, a multivariable analysis was performed. METHODS: Immunohistochemical staining for p53, HER-2/neu, estrogen receptor, progesterone receptor, and epidermal growth factor receptor was performed on frozen sections from 100 primary endometrial cancers. DNA ploidy was determined using computerized image analysis of Feulgen-stained touch preparations. In addition, information regarding surgical-pathologic features of the cancers was obtained. Univariable analysis was performed followed by multivariable analysis using Cox's proportional hazards model to identify variables predictive of poor prognosis. RESULTS: With univariable analysis, race, histologic type, stage, grade, myometrial invasion, estrogen receptor, progesterone receptor, ploidy, p53 and HER-2/neu were predictive of the presence of persistent or recurrent disease. In the multivariable analysis, only International Federation of Gynecology and Obstetrics stage (P = 0.005), grade (P = 0.005), myometrial invasion (P = 0.024), and ploidy (P = 0.028) were significant. CONCLUSIONS: Among molecular-genetic prognostic factors, DNA ploidy was the most strongly predictive of persistent or recurrent disease.

Aged↗
PubMed1994

Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression.

BACKGROUND: The p185c-erbB-2 growth factor receptor protein tyrosine kinase (PTK) is overexpressed in one third of human breast cancer patients and indicates a poor prognosis in these patients. Protein tyrosine phosphatases (PTPs) may balance PTK activity as part of normal growth-regulation pathways. PTP1B is an intracellular PTP that is involved in linkage between signal transduction pathways and may interface with inappropriate PTK activity in transformed cells. PURPOSE: The aim of this study was to determine if PTP1B is overexpressed in human mammary tumors and to determine if such overexpression is associated with the overexpression of the p185c-erbB-2 receptor PTK. METHODS: Our samples were frozen sections from 29 human mammary tumors (19 pure infiltrating, two pure intraductal, and eight combined intraductal and infiltrating) and nine sections from normal breast tissue. The sections were immunohistochemically stained for PTP1B and p185c-erbB-2, and the results were analyzed statistically for association between overexpression of the two proteins. Northern blot analysis was used to assess if PTP1B overexpression was coincident with increased transcription of the PTP1B gene. RESULTS: Overexpression of the PTP1B protein was observed in 72.4% of the tumor sections compared with normal epithelium, with maximal expression occurring in 37.9% of the tumors. All of the tumor subtypes, including the pure intraductal lesions, overexpressed PTP1B. Statistical analyses demonstrated a significant association between PTP1B overexpression and breast cancer (P < .038) and between the overexpression of PTP1B and the overexpression of p185c-erbB-2 (P < .006). PTP1B messenger RNA steady-state transcription was consistently increased in tumors versus normal tissues. CONCLUSIONS: PTP1B overexpression is a common phenotypic manifestation in human breast cancers and is associated with over-expression of p185c-erbB-2. Steady-state PTP1B transcription is increased in tumor tissue. IMPLICATIONS: Further studies are needed to determine if PTP1B overexpression balances or augments PTK activity. PTP1B overexpression might also be evaluated as a clinical prognostic factor in human breast cancers.

Blotting, Northern↗
PubMed1994

Secretion of extracellular matrix-degrading proteinases is increased in epithelial ovarian carcinoma.

The biochemical events associated with tumor invasion involve localized degradation of the basement membrane by tumor-associated proteinases. In this study, we have characterized the proteinase secretion profiles of 5 ovarian epithelial carcinoma cell lines (DOV 13, OVCA 420, OVCA 429, OVCA 432, OVCA 433) as well as normal ovarian epithelial cells. Immunocapture assays demonstrated that all 5 carcinoma cell lines produce both secreted and surface-associated plasminogen activator. Urinary-type plasminogen activator (u-PA) production was one order of magnitude greater than production of tissue-type plasminogen activator (t-PA). Furthermore, t-PA secretion by normal ovarian epithelial cells was not detectable, whereas u-PA production was 17- to 38-fold lower than in ovarian carcinoma cells. Western-blotting analysis demonstrated that u-PA was secreted as the single chain form (scu-PA) when cells were cultured in serum-free medium. Incubation of plasminogen with ovarian carcinoma cell-conditioned medium resulted in direct activation of the zymogen to plasmin. Furthermore, following incubation of cells with plasminogen, plasmin was eluted from the cell surface, indicating that ovarian carcinoma cells contain binding sites for plasminogen/plasmin which are accessible to surface-associated plasminogen activators. In addition to plasminogen activators, metalloproteinases were also produced by DOV 13, OVCA 429 and OVCA 433 cells. DOV 13 cells produce a 68-kDa metalloproteinase similar to matrix metalloproteinase 2 (MMP-2) whereas a 92-kDa enzyme similar to MMP-9 is secreted by OVCA 429 and 433. Together, ovarian carcinoma-associated plasminogen activators and metalloproteinases catalyze the hydrolysis of the major basement membrane protein components, type-IV collagen, type-IV gelatin, laminin and fibronectin. The enhanced proteolytic capability of ovarian carcinoma cells relative to normal ovarian epithelium suggests a biochemical mechanism by which invasion and spread of ovarian epithelial carcinoma may be mediated.

Blotting, Western↗
PubMed1994

Overexpression of p53 is not a feature of benign and early-stage borderline epithelial ovarian tumors.

Since overexpression of mutant p53 protein is a common feature of invasive epithelial ovarian cancers, we investigated whether overexpression of the p53 tumor suppressor gene product occurs in benign and borderline epithelial ovarian tumors. Immunohistochemical staining for p53 was performed in frozen samples of 17 benign tumors and in 49 borderline tumors (4 frozen, 45 paraffin embedded). Overexpression of p53 was observed in 0/17 (0%) benign ovarian tumors and 2/49 (4%) borderline tumors. Overexpression of p53 in borderline tumors was only seen in advanced stage cases; overexpression was seen in 2/8 (25%) stage III cases, but not in any of 41 stage I/II cases. In conclusion, overexpression of p53 is not a feature of benign epithelial ovarian tumors or early-stage borderline ovarian tumors. Similar to invasive epithelial ovarian cancers, however, a fraction of metastatic borderline tumors also overexpress p53.

Adult↗
PubMed1994

Transfection of ovarian cancer cells with tumor necrosis factor-alpha (TNF-alpha) antisense mRNA abolishes the proliferative response to interleukin-1 (IL-1) but not TNF-alpha.

Recombinant interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can induce endogenous TNF-alpha mRNA expression and stimulate proliferation of epithelial ovarian cancer cells. In a previous report, proliferation induced by either cytokine could be partially blocked by soluble TNF-alpha receptor or by neutralizing antibodies against TNF-alpha. In the present study, we have transfected the ovarian cancer cell line OVCA 432 with vectors that contain the TNF-alpha gene in the antisense or sense orientation. Antisense-transfected cells showed a 4.5- to 26-fold reduction in IL-1-induced TNF-alpha secretion. Similarly, the stimulation of [3H]thymidine incorporation by IL-1 but not by TNF-alpha was blocked by TNF-alpha antisense transfection. These results are consistent with a model in which the macrophage-derived cytokines IL-1 and TNF-alpha might stimulate endogenous production of TNF-alpha that in turn could stimulate proliferation of ovarian cancer cells by autocrine growth regulation.

Cell Division↗