estramustine and Body-Weight

Topics: Androgen Antagonists; Animals; Body Weight; Bone Marrow; Chlorocebus aethiops; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Estramustine; Estrogen Antagonists; Female; Lethal Dose 50; Macaca mulatta; Male; Mice; Mutagenicity Tests; Neoplasms, Experimental; Nitrogen Mustard Compounds; Rats; Reproduction; Salmonella typhimurium; Time Factors

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

Topics: Aged; Body Weight; Cardiovascular Diseases; Clinical Trials as Topic; Cyproterone; Cyproterone Acetate; Diethylstilbestrol; Estramustine; Europe; Humans; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Nitrogen Mustard Compounds; Prostatic Neoplasms; Random Allocation; Time Factors

Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor Ro 28-2653 has been shown in various models of different tumor entities. We hypothesized that the inhibitor effect of Ro 28-2653 on the tumor growth could be improved by combination with chemotherapeutic drugs and examined therefore the effect of Ro 28-2653 alone and in combination with etoposide or estramustine in the MatLyLu Dunning R-3327 rat tumor model characteristic for the androgen-independent prostate cancer (PCa).. In vitro effects were estimated measuring the proliferation of MatLyLu cells incubated with the three agents alone or in combination using the XTT test. The in vivo effects of the agents alone or in combination were examined by measuring the tumor weight 18 days after tumor cell injection.. The proliferation rate was only inhibited by etoposide while that effect was increased in combination with Ro 28-2653 and estramustine. Ro 28-2653 reduced the tumor weight by 86%. That effect was significantly increased in combination with etoposide to 92%.. The inhibitory effect of the MMP inhibitor Ro 28-2653 on the tumor growth in the Dunning PCa model is enhanced by the standard chemotherapeutic drug etoposide. A combined application of both agents could be considered as potential tool to improve the therapy of patients with advanced PCa after failure of hormonal treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Estramustine; Etoposide; Humans; Injections, Intraperitoneal; Male; Neoplasm Invasiveness; Neoplasm Transplantation; Piperazines; Prostatic Neoplasms; Pyrimidines; Rats; Time Factors; Tissue Inhibitor of Metalloproteinases

The present study was designed to determine if estramustine phosphate (EMP) could potentiate the effects of irradiation on the Dunning (R3327) prostatic adenocarcinoma in rats. Two groups of male Copenhagen x Fisher F1 rats carrying bilateral tumors in the flank were used. Irradiation was given with a linear accelerator 6 MV, in a dose of 6 Gy/day for 4 days to the tumor on one side while the tumor on the other side served as control. EMP (360 micrograms/24 hours) was administered with osmotic pumps to one group of rats for 2 weeks, starting 1 week before irradiation. Tumor growth was calculated by measuring tumor volume, and tumor blood flow was measured 8 weeks after treatment. Irradiation alone effectively delayed tumor growth and EMP enhanced these effects. Tumor blood flow was stimulated by EMP treatment irrespective of radiotherapy. Volume density of tumor epithelium was effectively decreased by irradiation but no significant effects could be seen after EMP. In conclusion, the present study shows that EMP potentiates irradiation on rat prostatic adenocarcinoma, and further evaluation of this therapeutic approach in the clinical treatment of prostatic carcinoma is thus justified.

Topics: Adenocarcinoma; Animals; Blood Pressure; Body Weight; Chemotherapy, Adjuvant; Epididymis; Estramustine; Male; Organ Size; Prostate; Prostatic Neoplasms; Rats; Regional Blood Flow; Testis; Testosterone

The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.

Topics: Adenocarcinoma; Adrenal Glands; Animals; Aromatase Inhibitors; Body Weight; Chlorobenzenes; Estradiol; Estramustine; Hypophysectomy; Male; Neoplasm Metastasis; Neoplasms, Experimental; Orchiectomy; Organ Size; Prostatic Neoplasms; Pyrimidines; Pyrrolidines; Rats; Rats, Inbred Strains; Seminal Vesicles; Testis; Thiophenes

The effects of estramustine phosphate on the ultrastructure of the rat ventral prostate closely resemble postcastration events, i.e., a decrease in cell size and secretory activities. The fibromuscular stroma, especially collagen fibers, appear to lose their adherence to adjoining muscle cells and fibroblasts. An infiltration of lymphocytes was noted in dilated regions of the fibromuscular stroma. There was an increase in cellular activity in the ventral prostate of rats treated with megestrol acetate with varying degrees of cellular atrophy and cytoplasmic disorganization. Squamous metaplasia was evident in one experimental group of MA-treated animals. Particles resembling mature C-type viruses were observed in several prostates from control and experimental animals.

Topics: Animals; Atrophy; Body Weight; Collagen; Cytoplasm; Drug Administration Schedule; Endoplasmic Reticulum; Epithelium; Estramustine; Golgi Apparatus; Male; Megestrol; Muscle, Smooth; Nitrogen Mustard Compounds; Prostate; Rats; Rats, Inbred Strains

Two types of experiments were performed to elucidate the estrogenic effect of estracyt on the ventral and immature rats that had received injections of testosterone; then changes in weight of accessory rats and changes in weight of the total body, the ventral and the dorsolateral prostates, and adrenal gland, and changes in activities of testosterone 5alpha-reductase, alkaline phosphatase, and arginase of both lobes of the prostates were examined. In the second experiment, estracyt was injected into castrates rats and immature rats that had received injections of testosterone; then changes in weight of accessory sex organs were determined. Because similar changes were induced by treatment of animals with estradiol-17beta, it was concluded that the effect of estracyt on the prostates was most likely attributable to the estrogenic effect of the drug.

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenal Glands; Alkaline Phosphatase; Animals; Arginase; Body Weight; Castration; Estradiol; Estramustine; Male; Nitrogen Mustard Compounds; Organ Size; Prostate; Rats; Testis