metribolone and Ovarian-Neoplasms

The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR

Topics: Animals; Drug Discovery; Female; Hormone Antagonists; Humans; Mice; Ovarian Neoplasms; Rats; Receptors, Glucocorticoid; Swine; Swine, Miniature; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Cytosols of 94 untreated common epithelial ovarian cancer tissues were analysed for the presence of estrogen-, progesterone- and androgen receptors. Androgen receptors clearly predominated (90%) over and above estrogen- (55%) and progesterone receptors (52%). Further characterisation particularly of the androgen receptor revealed steroid-receptor complex with the sedimentation coefficient similar to ovalbumin (3,6 S). Only androgens, natural and synthetic, were able to alter the sedimentation profile. Estrogen appeared to slightly lower the peak, while progesterone and cortisol did not alter the profile at all. No difference in receptor concentrations between tumor tissues from pre-, peri- and postmenopausal women was found. The serum hormone levels (estradiol-17 beta, testosterone, FSH, LH) measured preoperatively in 20 postmenopausal patients did not correlate with the receptor status. Majority of the ovarian carcinomas studied contained androgen receptors. We therefore suggest consideration of the addition of anti-androgens to the therapeutic strategies applicable to ovarian cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cytosol; Dihydrotestosterone; Estrenes; Female; Humans; Metribolone; Middle Aged; Ovarian Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone

We have used in vivo and in vitro procedures to select a subpopulation of cells from the human ovarian carcinoma cell line, NIH:OVCAR-3, with the capacity to grow i.p. in female nude athymic mice. After i.p. injection of these cells, animals develop metastatic spread similar to that of clinical ovarian cancer. Disease progression is characterized by the development of massive ascites, extensive invasive i.p. tumors, and pulmonary metastases. The malignant ascites cells are transplantable, manifest cytoplasmic androgen and estrogen receptors, and express the ovarian cancer associated antigen CA125 (116,000 units/ml of ascites supernatant). The cells also have the same chromosome markers which were present in the original cell line, NIH:OVCAR-3. Survival following i.p. passage of ascites is dependent on tumor cell inoculum ranging from a median survival of 39 days with 40 million cells to 84 days for 11.5 million transplanted cells. The characteristics of this unique in vivo model make it well suited for the evaluation of new drugs and novel experimental therapies in ovarian cancer. In addition, this in vivo model, together with ovarian cancer cell lines, may prove particularly useful for the study of pharmacological ways to specifically increase the cytotoxicity of anticancer agents in tumor cells while not increasing toxicity in normal tissues. The presence of hormone receptors should facilitate the experimental evaluation of hormonal therapy in ovarian cancer.

Topics: Animals; Antigens, Neoplasm; Cytosol; Estradiol; Estradiol Congeners; Estrenes; Female; Humans; Metribolone; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Receptors, Estrogen; Transplantation, Heterologous

A cell line, NIH:OVCAR-3, has been established from the malignant ascites of a patient with progressive adenocarcinoma of the ovary after combination chemotherapy with cyclophosphamide, Adriamycin, and cisplatin. OVCAR-3 grows as a cobblestone-like monolayer with foci of multilayering, is tumorigenic in athymic mice, clones in agarose, and has an abnormal karyotype which includes a homogeneous staining region and a double minute chromosome. The cultured cells and xenografts contain cytoplasmic androgen- and estrogen-binding macromolecules with the specificity of the respective steroid hormone receptors. These components have sedimentation coefficients of 7 to 9S in low-salt sucrose-density gradients, have dissociation constants of 250 and 9.6 pM, and are present at concentrations of 30 and 28 fmol/mg cytosol protein characteristic of androgen and estrogen receptors, respectively. OVCAR-3 is resistant in vitro to clinically relevant concentrations of Adriamycin (5 X 10(-8) M), melphalan (5 X 10(-6) M), and cisplatin (5 X 10(-7) M) with survival compared to untreated controls of 43, 45, and 77%, respectively. Furthermore, there are multiple histological similarities between the patient's original tumor, the cell line, and the transplantable tumor. These data indicate that OVCAR-3 may be of use for investigations as to the significance of androgens and estrogens and the mechanisms of cytotoxic drug resistance in ovarian cancer.

Topics: Cell Division; Cell Line; Cell Survival; Cisplatin; Culture Techniques; Cytosol; Doxorubicin; Estradiol; Estrenes; Female; Humans; Karyotyping; Melphalan; Metribolone; Ovarian Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid