diethylstilbestrol-monophosphate and Prostatic-Neoplasms

Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs.. RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs).. HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs.. Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Male; Mice; Nitriles; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; RNA, Small Interfering

Topics: Antineoplastic Agents; Diethylstilbestrol; Humans; Male; Prostatic Neoplasms

We treated a patient in whom a hepatocellular carcinoma and a hyperplastic nodule of the liver concomitantly grew in association with long term phosphate diethylstilbestrol therapy for a carcinoma of the prostate. A 72-year-old Japanese man was admitted for investigation of hepatic masses. A diagnosis of prostate carcinoma had been made seven years ago and phosphate diethylstilbestrol 200 mg daily had been prescribed. A small mass was first detected in the liver four years later and another mass appeared three years after the appearance of the first mass. Histology of the excised tissue showed the former mass to be a hyperplastic nodule and the latter one hepatocellular carcinoma. Findings of cirrhosis, hepatitis or fibrosis were nil but fatty metamorphosis of the hepatocytes was apparent. These histological changes were considered to be associated with long-term phosphate diethylstilbestrol therapy therefore careful follow-up using amazing diagnosis is recommended for patients on phosphate diethylstilbestrol therapy.

Topics: Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Diethylstilbestrol; Humans; Hyperplasia; Liver; Liver Neoplasms; Male; Prostatic Neoplasms

For many years, diethylstilbestrol (DES) and its diphosphate (DESPP; Honvan) have been standard therapies for prostatic carcinoma. The effects of DES, its monophosphate (DESP) and of DESPP on the weights of accessory sex organs of mice and rats, and on the experimental Noble Nb-H and Nb-R prostatic carcinomas of the rat were, therefore, compared. In intact mature mice, all three compounds led to a strong and dose-dependent inhibition of seminal vesicle weights and testosterone levels, whereas only a slight antiandrogenic activity in castrated mice was found. In intact rats, DES, DESP and DESPP strongly inhibited accessory sex organ weights and testosterone levels. In castrated rats, however, no antiandrogenic activity was determinable. The prostate carcinoma-inhibiting effects of DES and DESPP were tested in comparison with castration in the transplantable hormone-sensitive Nb-H and Nb-R prostatic carcinoma in rats. Whereas castration caused only a retardation of tumor growth, DES and DESPP (3 x 0.1 mg/kg and 1.0 mg/kg weekly s.c.) led to an almost complete inhibition, which was significantly (P less than 0.01) better than the effect of castration. As the weights of accessory sex organs were identically reduced by either castration or the estrogens, a direct tumor-inhibiting effect of DES and DESPP in addition to their testosterone-lowering activity is obvious. This was proved in an experiment with castrated rats. The only slightly inhibitory activity of castration was strongly potentiated by concomitant administration of DES. Moreover, histological examinations revealed that Nb-H and Nb-R tumors were much more damaged by treatment with DES or DESPP than after castration. Morphometry of the tumors showed that tumor reduction is associated with a decrease in the ratio of the epithelial to the stromal density, i.e. there was an even more pronounced decrease in epithelial cells than that found by merely measuring tumor area. These studies show that the prostate carcinoma-inhibiting effect of DES and DESPP in the Nb model is superior to the effect of castration and that they act directly on the tumor cells used, even in castrated rats.

Topics: Androgen Antagonists; Animals; Carcinoma; Diethylstilbestrol; Genitalia, Male; Male; Organ Size; Prostatic Neoplasms; Rats; Rats, Inbred Strains; Receptors, Androgen; Tamoxifen

To evaluate a possible direct cytotoxic effect of diethylstilbestrol diphosphate (DESDP) in the treatment of prostate cancer we exposed three prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3), 2 nonprostatic neoplastic cell lines (KB and EJ), and one nontransformed cell line (MRC-5) to diethylstilbestrol (DES), diethylstilbestrol monophosphate, and DESDP at levels occurring in patients' sera during p.o. DES therapy (2 to 5 ng/ml) or DESDP infusions (1 to 20 micrograms/ml), respectively. With 5 ng/ml of DES no effect was seen in LNCaP cells, even after 14 days of exposure. In contrast, drug levels attained during DESDP infusions showed marked, dose-dependent cytotoxicity towards all cell lines under study. Prostatic cells were not exceptionally sensitive. High-dose DES slightly stimulated the synthesis of prostatic acid phosphatase in LNCaP cells. Formation of foci of polygonal cells was induced by 5 micrograms/ml of DES in cultures of MRC-5 fibroblasts. We conclude that, at high doses, DES liberated from DESDP acts upon a regulatory or metabolic mechanism common to many if not all human cells. Preferential sensitivity of prostate cancer cells in vivo may be due to high local phosphatase activity and/or DES accumulation in prostatic tissue.

Topics: Acid Phosphatase; Antineoplastic Agents; Diethylstilbestrol; Humans; Male; Phosphoric Monoester Hydrolases; Prostate; Prostatic Neoplasms; Tumor Cells, Cultured

This paper reports an autopsy case of a 78-year-old male with multiple nodules in the liver developed after long-termed administration of phosphate diethylstilbestrol (PDES) for prostatic cancer. Large part of these nodules were suspected to be well differentiated hepatocellular carcinoma with high level of serum alpha-fetoprotein (AFP) up to 3,400 ng/ml, but a part of them was evaluated to be a borderline between hepatocellular carcinoma and adenoma with mild cellular atypism. The liver other than the nodules showed liver fibrosis associated with liver cell dysplasia and peliosis hepatis-like change. This is a unique autopsy case of hepatocellular carcinoma closely related to diethylstilbestrol (DES) therapy for prostatic cancer.

Topics: Adenoma; Aged; alpha-Fetoproteins; Carcinoma, Hepatocellular; Diethylstilbestrol; Humans; Liver; Liver Neoplasms; Male; Prostatic Neoplasms