epidermal-growth-factor and Genital-Neoplasms--Female

Antibody-drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Epidermal Growth Factor; Female; Genital Neoplasms, Female; Humans; Immunoconjugates; Receptor, ErbB-2

EGF-related peptides and their receptors play an important, but not fully understood role, both, in epithelial physiology and pathophysiology but also in human tumor carcinogenesis and tumor behavior, respectively. Overexpression of EGF-related growth factors from normal epithelium to carcinomas has been demonstrated for several human tissues such as breast, endometrium, cervix and ovary. Additionally, the differential overexpression of EGFR or erb B-2 in various malignancies has already proven to be efficacious in stratifying patients with respect to a poor prognosis. These data suggest that EGF-related growth factors, erb B receptors or signaling proteins that function either upstream or downstream from these receptors may represent novel targets for selective tumor therapy. In the future, conventional chemotherapy regimes will ultimately be wedded to more biologically-oriented therapies. One important target for these novel therapeutic approaches in solid tumors will be the EGF-related growth factors and their receptors.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Female; Genital Neoplasms, Female; Humans; Receptor, ErbB-2; RNA, Messenger; Transforming Growth Factor alpha

During the past 30 years, a number of growth factors have been isolated and characterized. These include insulin and insulin-like growth factors, the fibroblast growth factors, the hematopoietic colony-stimulating growth factors, and the epidermal growth factor (EGF) group. Epidermal growth factor, which stimulates the growth of a variety of tissues, has been extensively studied since its discovery in the early 1960s. This review presents an historic perspective, basic scientific aspects, laboratory methods, and the clinical application of EGF in the specialty of obstetrics and gynecology. Expanding research on this factor together with its increasing clinical applications will undoubtedly predict its routine use in clinical practice. Understanding basic and applied knowledge of EGF will become essential for clinicians in adapting this new technology to patient care.

Topics: Amniotic Fluid; Epidermal Growth Factor; ErbB Receptors; Female; Genital Neoplasms, Female; Humans; Placenta; Pregnancy; Pregnancy Trimester, Third; Sex Factors; Uterus; Wound Healing

The purpose of this study is to develop a high-throughput approach to detect protein expression from hundreds and thousands of samples and to apply this technology to profile circulating angiogenic factor protein levels in patients with gynecological tumors.. Analytes containing a mixture of protein are immobilized onto antibody-coated surface of support in array format. The presence of protein in analytes is detected with biotin-labeled antibody coupled with an enhanced chemiluminescence or fluorescence detection system. The exact amount of protein can be quantitatively measured. The expression levels of five angiogenic factors (angiogenin, interleukin 8, vascular endothelial growth factor, platelet-derived growth factor, and epidermal growth factor) from 157 samples were quantitatively measured using this novel protein array technology and were statistically analyzed. The expression patterns of angiogenic factors were analyzed using two-way hierarchical cluster analysis approach.. A novel protein array technology, which can simultaneously and quantitatively measure few protein levels from hundreds and thousands of samples was developed. Only minute amounts of sample are required for the assay. This approach also features high sensitivity and specificity. Using this novel protein array approach, we analyzed the plasma expression levels of five angiogenic factors in 137 patients diagnosed with a tumor and 20 controls. Statistical analysis reveals different expression levels of angiogenic factors between patients and controls. Cluster analysis suggests a possible classification of normal subjects from patients.. Enhanced protein profiling arrays provide a high-throughput and sensitive system to detect one or few protein from hundreds and thousands of samples. Such an approach should have broad application in biomedical discovery.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biotin; Cell Line, Tumor; Cluster Analysis; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Genital Neoplasms, Female; Humans; Immunoglobulin G; Interleukin-8; Luminescent Measurements; Microscopy, Fluorescence; Middle Aged; Multigene Family; Neoplasms; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Platelet-Derived Growth Factor; Protein Array Analysis; Ribonuclease, Pancreatic; Sensitivity and Specificity; Tissue Distribution; Vascular Endothelial Growth Factor A

Spontaneous and epidermal growth-factor-induced proliferation of human gynecological cancer cell lines is dose- and time-dependently reduced by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist triptorelin and antagonist Cetrorelix. This antiproliferative activity is probably directly mediated through the LHRH receptors expressed by the tumor cells interacting with growth-factor-dependent mitogenic signal transduction. We have examined whether epidermal growth-factor (EGF)-induced expression of the early response gene c-fos is reduced by LHRH analogs.. Human endometrial (Ishikawa, Hec-1A), ovarian (EFO-21, EFO-27, SK-OV-3), and breast cancer cell lines (MCF-7) were rendered quiescent by incubation (72 h) in the absence of fetal calf serum and phenol red. This was followed by a 15-min incubation in the absence or presence of the LHRH agonist triptorelin (100 nM) or the antagonist Cetrorelix (100 nM) before the cells were stimulated for 10 min with EGF (100 nM). C-fos mRNA expression was determined by semi-quantitative RT-PCR using a synthetic DNA fragment as internal standard. C-Fos protein synthesis was determined by SDS-PAGE and semi-quantitative Western blotting.. In cells derived from endometrial and ovarian cancer, maximal c-fos mRNA expression (seven- to ninefold over basal level) was obtained 30 min after EGF stimulation. In the breast cancer cell line MCF-7 this effect was obtained 60 min after EGF treatment. In all of the lines expressing LHRH receptor, EGF-induced c-fos mRNA expression as well as c-Fos protein synthesis was dose-dependently reduced by treatment with LHRH agonists and antagonists. At 100 nM concentrations of the LHRH analogs, c-fos expression was reduced to baseline levels. No effect of LHRH analogs on EGF-induced c-fos expression was observed in the ovarian cancer cell line SK-OV-3, which does not express the LHRH receptor.. These results suggest that the binding of LHRH agonists and antagonists to their receptors inhibits the mitogenic signal transduction pathway of the EGF receptor in endometrial, ovarian, and breast cancer cell lines. The coupling of both signal transduction systems mediates the antiproliferative effect of LHRH analogs.

Topics: Antineoplastic Agents, Hormonal; Down-Regulation; Epidermal Growth Factor; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, fos; Genital Neoplasms, Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Luteolytic Agents; Proto-Oncogene Proteins c-fos; Receptors, LHRH; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triptorelin Pamoate; Tumor Cells, Cultured

We investigated the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on migration, invasion and proteinase expression of gynecological cultured cancer cells (SKG-IIIb cervical squamous cell carcinoma, OMC-4 cervical adenocarcinoma, SNG-M endometrial adenocarcinoma and OMC-3 ovarian adenocarcinoma), and whether these growth factors affect thymidine phosphorylase/platelet-derived endothelial cell growth factor expression of tumor cells. Tumor cell migration along a gradient of substratum-bound fibronectin and invasion into reconstituted basement membrane were stimulated by 0.1-10 nM EGF and TGF-alpha in a concentration-dependent manner. The zymography of tumor-conditioned medium showed that the treatment of tumor cells with EGF and TGF-alpha resulted in the increase of type IV collagenases, stromelysin and urokinase-type plasminogen activator which was partly confirmed by immunoblot analysis. The expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor which has angiogenic activity, was also upregulated by these growth factors. These results suggest that EGF and TGF-alpha act as positive regulators on the invasion process of gynecological tumor cells which may be associated with their stimulatory action on the motility of tumor cells, the expression of proteinases secreted by tumor cells and the angiogenic phenotype.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Cell Movement; Endometrial Neoplasms; Epidermal Growth Factor; Female; Genital Neoplasms, Female; Humans; Metalloendopeptidases; Neoplasm Invasiveness; Ovarian Neoplasms; Thymidine Phosphorylase; Transforming Growth Factor alpha; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator; Uterine Cervical Neoplasms

The regulation of parathyroid hormone-related protein (PTH-rP) mRNA levels and immunoreactive (ir)PTH-rP formation by peptide growth factors, particularly transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF), in squamous cell carcinomas of gynecologic origin is largely unknown.. PTH-rP mRNA levels were evaluated by Northern analysis in A431 cells (derived from a human vulvar epidermoid carcinoma) and ME-180 cells (derived from a human papillomavirus-infected squamous cell carcinoma of the cervix). PTH-rP protein levels in cell culture media were evaluated using both radioimmunoassay and immunoradiometric assay techniques. These results were compared with those from a lung carcinoid cell line known to produce PTH-rP, namely, NCI-H727 cells.. TGF-beta 1 or EGF treatment caused an increase in the levels of PTH-rP mRNA in A431 cells; these increases in PTH-rP mRNA were detectable after 60 minutes of treatment, were maximal at approximately 4-8 hours, and were approximately additive. Immunoreactive PTH-rP was not detectable (using two different PTH-rP immunoassays) in the culture medium or cell sonicates of A431 cells before or after treatment with TGF-beta 1, EGF, or TGF-beta 1 plus EGF. ME-180 cells responded to EGF (but not to TGF-beta 1) with an increase in the level of PTH-rP mRNA as early as 2 hours; irPTH-rP was present (by use of either immunoassay) in the medium of these cells at 8 and 24 hours. In NCI-H727 (human lung carcinoid) cells, TGF-beta 1 and EGF acted alone and synergistically to effect increases in PTH-rP mRNA and the accumulation of irPTH-rP.. TGF-beta 1 and EGF regulation of PTH-rP gene expression in squamous cell carcinomas of gynecologic origin is unique for each cell line studied and different from that in human lung carcinoid cells.

Topics: Base Sequence; Carcinoid Tumor; Carcinoma, Squamous Cell; Epidermal Growth Factor; Female; Gene Expression Regulation, Neoplastic; Genital Neoplasms, Female; Humans; Lung Neoplasms; Molecular Sequence Data; Neoplasm Proteins; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Proteins; RNA, Messenger; Transforming Growth Factor beta; Tumor Cells, Cultured; Uterine Cervical Neoplasms; Vulvar Neoplasms

The trophoblast of the human placenta is composed of two layers: syncytiotrophoblast and cytotrophoblast. Cytotrophoblast displays highly proliferative and invasive properties, while syncytiotrophoblast displays little potential for proliferation. Regulatory factors involved in processes of proliferation and differentiation of the trophoblast still remain to be elucidated. Immunohistologically, myc product was predominantly localized to cytotrophoblastic cells. A close similarity between cytologic localization of myc product and tritiated thymidine labeling of placental explant suggests that myc protein expression is linked to trophoblast proliferation. A similar pattern of cytological localization was observed with the use of anti-PDGF antibody, supporting a possibility that PDGF also plays a role in the trophoblast proliferation. Human trophoblast produces two major proteins, hCG and hPL. hCG stimulates progesterone production by corpus luteum. hPL exerts lipolytic action which assures glucose supply to the fetus. In situ hybridization with cDNA probes for hCG(alpha, beta) and hPL revealed that mRNA expression of hCG alpha and probably hCG beta are initiated before syncytial formation, whereas hPL mRNA is expressed only in fully differentiated syncytiotrophoblast. hCG levels in maternal serum are the highest in early pregnancy and thereafter decline, while hCG alpha and hPL levels increase throughout pregnancy. In patients with choriocarcinoma, serum hPL levels are extremely low despite high levels of hCG. In this context, hCG beta mRNA levels remarkably declined in term placenta compared to early placenta, and hPL mRNA was little observed in choriocarcinoma. EGF and EGF receptor (EGF-R) in 4-5 weeks placenta were almost exclusively localized to cytotrophoblasts, whereas EGF and EGF-R in 6-12 weeks placenta were predominantly localized to syncytiotrophoblasts. In the second and third trimester placentas, EGF was mainly localized to cytotrophoblasts, while EGF-R was predominantly localized to syncytiotrophoblasts. It is of great interest that the cytologic localization of EGF and EGF-R in human placenta varies according to the age of gestation. The fact that mitotically active cytotrophoblasts in 4-5 weeks placenta were positive for both EGF and EGF-R expression suggests that EGF and EGF-R may be involved in the control of multiplication of cytotrophoblasts very early in the first trimester. On the other hand, the fact that mitotically inactive syncytiot

Topics: Biomarkers, Tumor; Cell Differentiation; Cell Division; Chorionic Gonadotropin; Chorionic Gonadotropin, beta Subunit, Human; Corticotropin-Releasing Hormone; Epidermal Growth Factor; Female; Genes, myc; Genital Neoplasms, Female; Humans; Peptide Fragments; Pregnancy; Trophoblasts

Manifestation of EGF receptors and enhancement of an anticancer agent by EGF were studied in cultured cells derived from female genital cancers. 1) The numbers of EGF-receptors of SKG-3a, RMUG-s, HUOA, A-431 and HEC-1 were 1.22 x 10(4), 6.94 x 10(4), 2.75 x 10(4), 5.25 x 10(5) and 0.92 x 10(4) sites per cell respectively. The values for the dissociation constant (Kd) of RMUG-s, SKG-3a, HUOA and HEC-1 were 340pM, 477pM, 989pM and 2,187pM, respectively. 2) All cell lines were stimulated by EGF at low concentrations and inhibited at higher concentrations. The growth stimulation rates for SKG-3a, HEC-1, HUOA and RMUG-s in the presence of 0.01 nM EGF at 48 hours were 8, 18, 21.1 and 3.7%, respectively. The growth inhibition rates for SKG-3a, A-431, HEC-1, HUOA and RMUG-s in the presence of 1.0 nM EGF at 48 hours were 32, 28, 25.8, 11.2 and 6.8%, respectively. 3) The antitumor effect of CDDP was enhanced by the presence of EGF at both a concentration of 0.01 nM (except for A-431) and a concentration of 1.0 nM, in all cell lines. 4) EGF receptors of RMUG-s and HUOA were decreased by CDDP. The values for RMUG-s and HUOA were 1.71 x 10(4), 0.52 x 10(4) (CDDP 0.4 microgram/ml) and 0.95 x 10(4), 0.29 x 10(4) sites per cell (CDDP 2.0 micrograms/ml), respectively. The effect of CDDP on EGF receptors was not recognized in SKG-3a and HEC-1. In brief, EGF receptors were significantly expressed in cell lines derived from female genital cancers.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cell Cycle; Cisplatin; Drug Synergism; Epidermal Growth Factor; ErbB Receptors; Female; Genital Neoplasms, Female; Humans; Tumor Cells, Cultured