Evaluation of the Cytotoxic Activity of Diethylstilbestrol and Its Phosphorylated Derivatives towards Prostatic Carcinoma, Non-Prostatic Neoplastic and Non-Transformed Cells

Abstract

Infusion of high doses of diethylstilbestrol-diphosphate (DESDP) administered to patients relapsing on conventional androgen-suppressing therapy of carcinoma of the prostate often leads to significant improvement of the patient’s quality of life. The benefits of DESDP have been ascribed to its specific cytotoxic activity towards prostatic carcinoma cells. To evaluate the tissue specificity of the cytotoxic effect, we exposed three prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3), three non-prostatic neoplastic cell lines (KB: epidermoid carcinoma, EJ: Bladder carcinoma, Daudi: Burkitt lymphoma), and one non-transformed embryonic fibroblast line (MRC-5) to diethylstilbestrol (DES), DES monophosphate, and DESDP, at levels comparable to those occurring in patients’ sera during DESDP infusions. At concentrations of 1–20 µg/ml the drugs showed marked, dose-dependent cytotoxicity towards all cell lines under study. The variation of the magnitude of the response among the different cell lines was considerable. In LNCaP cells the synthesis of prostatic acid phosphatase was monitored. We found that DES slightly stimulates prostatic acid phosphatase production. Formation of focuses of polygonal cells in MRC-5 cultures was induced by 7.5 µg/ml DES monophosphate. We conclude that at high doses DES liberated from DESDP acts upon a general biochemical or regulatory pathway. Preferential sensitivity of prostate cancer cells in vivo may be due to high local phosphatase activity and/or DES accumulation in prostatic tissue.

Synthetic androgens suppress the transformed phenotype in the human prostate carcinoma cell line LNCaP

“…All experimental data obtained with physiological androgen concentrations are consistent with inhibition of proliferation triggered by an androgen receptor-dependent mechanism. Since synthetic derivatives of steroid hormones can act as directly cytotoxic agents (Schulz et al, 1988a), we examined, whether the inhibitory effect of synthetic androgens toward LNCaP cells is specific for this androgen receptor positive cell type. All control cell lines devoid of androgen receptors were in no way affected by the androgens tested.…”

“…Cell culture and assays for inhibition ofproliferation Assays were carried out with media containing 10% complete FCS as described in detail (Schulz et al, 1988a Assay for anchorage-independent growth Agar Noble (Difco) was suspended at 0.75% in water, autoclaved, and cooled to 60°C. 1/10 volune of 10-fold concentrated Dulbecco's medium and 1/10 volume of FCS were added, and 3 ml of this solution (0.6% agar) were poured into a culture dish of 60 mm diameter.…”

The role of estrogens and estrogen receptors in normal prostate growth and disease

“…Thus many estrogens including phytoestrogens, DES and 2-methoxyestradiol as well as selective estrogen receptor modulators (SERMs) including raloxifene, ICI 182,780, trioxifene and torimifene have been shown to affect prostate tumor growth through a variety of mechanisms [20,[120][121][122][123][124][125][126]. While initial clinical trials using tamoxifene and toremifene proved to be unremarkable for the treatment of prostate disease [127,128], more recent Phase II studies indicate that the toremifene may in fact effectively block development and progression of clinical prostate cancer and further clinical trials are underway [126,129].…”

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

“…This finding raised the possibility that estrogens might have additional oncologic benefits. DES was shown to have direct cytotoxic effects on PCa cells in concentrations achieved in vivo by very high-dose infusions, historically used with palliative benefit in patients, although this may have been a non-ER-mediated pharmacological effect (Schulz et al 1988, Robertson et al 1996, Geier et al 2010.…”