acid-phosphatase and fosfestrol

Androgen deprivation displays the mean therapy of advanced stage prostatic cancer. The development of hormone-resistant disease leads to a fatal tumor progression. High-dose fosfestrol (diethylstilbestrol disphosphate) has been suggested to circumvent hormone resistance and to induce a direct cytotoxic effect. Twenty-one patients with hormone-refractory prostate cancer were enrolled in a phase I trial of continuous infusion of high, daily escalating dose of fosfestrol. Fosfestrol was given in a 3.5 hr infusion in 0.9% normal saline at a starting dose of 1.5 g/d. The dose was increased daily in the same patient according to the following schedule: 1.5, 1.8, 2.4, 3.0, 3.6, 3.9, 4.5, 5.1 and 5.7 g/d. The duration of the infusion was prolonged to 7 or 10.5 hr, if a major side effect occurred. There was neither hematological nor cardiovascular toxicity. The main dose-limiting toxicities were nausea/vomiting in 17 patients, edema in 2 patients, and more than 5% weight gain in 3 patients. The planned maximal dose was reached in 10 patients during a 3.5 hr infusion, and in 3 additional patients, after infusion prolongation. Seven patients experienced a subjective improvement: Prostatic acid phosphatase and prostatic specific antigen decreased in 4 out of 11 and in 7 out of 12 patients, respectively. The suggested dose to phase II trial is 4 g/d in 3.5 hr infusion for a duration of up to 10 days.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Antineoplastic Agents; Biomarkers, Tumor; Bone Neoplasms; Combined Modality Therapy; Diethylstilbestrol; Drug Resistance; Humans; Infusions, Intravenous; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Orchiectomy; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms

In previous work (P. Schulz et al., Cancer Res., 48: 2867-2870, 1988) we have demonstrated that diethylstilbestrol (DES), DES-monophosphate, and DES-diphosphate (DESDP) are generally cytotoxic at concentrations attained in patients' sera during therapeutic DESDP infusions for progressed carcinoma of the prostate. We have extended this work and addressed two questions: (a) Is DESDP itself a completely nontoxic prodrug which has to be transformed into the active species DES by a phosphatase? (b) Which metabolic or regulatory mechanism in a cell is the target of DES action? Using cell cultures in phosphatase-depleted media we could provide evidence that DESDP exerts cytotoxic activity only after conversion to DES. Oxygen electrode experiments and difference spectra with intact mitochondria demonstrated that DES did not act as an uncoupler, but inhibited electron flow from ubiquinone to cytochrome c1. Phenomena previously observed in DES-treated cells could be explained by distortion of the energy metabolism.

Topics: Acid Phosphatase; Animals; Antineoplastic Agents; Cattle; Cell Line; Cell Survival; Culture Media; Diethylstilbestrol; Electron Transport Complex III; Hot Temperature; Humans; Kinetics; Male; Mitochondria, Heart; Mitochondria, Liver; Oxygen Consumption; Prostatic Neoplasms; Rats; Tumor Cells, Cultured

The correlation between tumor volume of untreated tumor-bearing nude mice and serum concentration of prostatic acid phosphatase (PAP/RIA) was studied in the hormone-dependent serially transplantable human prostatic tumor models PC-82 and PC-EW. The normal serum level of PAP in control male nude mice without tumor was found to be 0.9 +/- 0.3 ng/ml. Elevated PAP serum concentrations were never found in animals without tumor (a highly specific diagnostic technique). A close correlation was observed between the concentration of PAP in the serum (range 0.3 to 154 ng/ml) and the tumor volume (range 10.0 to 6,530 mm3) of 104 untreated mice bearing a PC-82 or PC-EW human prostatic tumor. This correlation was comparable in both tumor lines (p less than 0.001). The positive effect of endocrine manipulation which resulted in tumor diameter decrease or growth arrest with regressive histological patterns, showed the normal PAP serum level, too. After successful treatment PAP was found to be normal, independent from the residual tumor mass. By contrast, in the event of only retarded tumor growth, the PAP level still correlated with the tumor burden.

Topics: Acid Phosphatase; Animals; Antineoplastic Agents; Cell Line; Diethylstilbestrol; Estrogen Antagonists; Humans; Indoles; Male; Mice; Mice, Nude; Neoplasm Transplantation; Orchiectomy; Prostatic Neoplasms; Tumor Cells, Cultured

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

Twenty-five patients with metastatic prostate cancer resistant to primary hormone therapy, received high-dose intravenous diethylstilbestrol diphosphate (Stilphostrol [Miles Pharm], DES-P) in a Phase II study using established response criteria. Objective response rate was 17%, while 22% of the patients were subjectively improved. Moderate gastrointestinal toxicity was reported in 10 patients (40%). Thromboembolic complications were seen in 2 (8%). The role of high-dose Stilphostrol in the treatment of hormone-resistant prostate cancer is limited.

Topics: Acid Phosphatase; Adenocarcinoma; Aged; Antineoplastic Agents; Bone Neoplasms; Castration; Combined Modality Therapy; Diethylstilbestrol; Dose-Response Relationship, Drug; Drug Evaluation; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms

The levels of plasma testosterone, testosterone-oestradiol binding globulin (TeBG) and total serum acid phosphatase (TSAP) following antiandrogenic hormone therapy were investigated in 17 patients with prostatic carcinoma. The low levels of plasma total and free testosterone induced by castration decreased further after diethylstilboestrol diphosphate (DES-D) administration. Plasma TeBG binding capacity after castration was 118.9% of the pre-treatment level and increased to 193.9%, 204.0% and 212.7% at 1, 2 and 3 weeks after DES-D dosing. The in vitro binding of 3H-testosterone to TeBG was not influenced in the presence of DES-D or stilboestrol. Clinical response following the DES-D therapy was associated with a decrease in the levels of TSAP. A significantly inversed correlation was found between the decrease in TSAP and increase in TeBG at completion of DES-D therapy. These results suggest that the high binding capacity of TeBG lowers the biologically active fraction of testosterone and thus may produce clinical effects.

Topics: Acid Phosphatase; Castration; Diethylstilbestrol; Electrophoresis, Polyacrylamide Gel; Humans; Male; Prostatic Neoplasms; Sex Hormone-Binding Globulin; Testosterone

Thirty-six patients with prostatic carcinoma and benign prostatic hyperplasia (BPH) were studied. Transurethral resection (TUR) was performed in all, and serum and tissue ribonuclease (RNase) levels were determined with the spectrophotometric method using yeast RNA as the substrate. In patients with untreated prostatic carcinoma, statistically significant increased RNase levels were found in serum and tissue. Treatment with diethylstilbestrol diphosphate (DESDP) led to a decrease in RNase levels. In the same patients RNase serum levels after DESDP treatments also showed a parallel decrease with serum prostatic acid phosphatase (sPAP) levels. We have concluded that the serum RNase measurement may be useful for TNM classification and immunostaging.

Topics: Acid Phosphatase; Diethylstilbestrol; Humans; Hyperplasia; Male; Probability; Prostate; Prostatic Neoplasms; Ribonucleases

Topics: Acid Phosphatase; Chlorotrianisene; Diethylstilbestrol; Humans; Injections, Intravenous; Male; Neoplasm Metastasis; Neoplasms; Palliative Care; Prostatectomy; Prostatic Neoplasms; Toxicology; Urination Disorders