estramustine and Disease-Models--Animal

Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgens; Animals; Antineoplastic Agents; Arginase; Dihydrotestosterone; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Estradiol; Estramustine; Estriol; Estrogens; Flutamide; Haplorhini; Humans; Male; Mice; Neoplasms, Experimental; Prostate; Prostatic Neoplasms; Rats; Testosterone

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

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

Therapeutic efficacy of the novel matrix metalloproteinase (MMP) inhibitor, Ro 28-2653 (5-biphenyl-4-yl-5-[4-(-nitro-phenyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione), has been shown in various models of different tumor entities. The tumor growth-reducing effect has been demonstrated in the orthotopic rat prostate Dunning model (subline MatLyLu). Based on these results we investigated Ro 28-2653 in combination with estramustine on the G subline of the Dunning tumor. This subline is characterized by a low metastatic ability and androgen sensitivity. Efficacy was determined by recording tumor growth in vivo by magnetic resonance imaging (MRI). Tumor cells were injected into the prostates of 81 Copenhagen rats. MRI was performed at day 100 and at day 126 after tumor cell injection. The duration of therapy was 17 days with daily oral application of Ro 28-2653 (100 mg/kg) and four i.p. injections of estramustine (7.5 mg/kg). Histological evaluations were conducted to provide further information about the effects on tumor morphology. Orthotopic tumor induction was successful in 100% of the animals. Tumor volume calculations with MRI showed a significant difference between the control groups, the animals treated with Ro 28-2653, and the animals treated with the combination of Ro 28-2653 and estramustine. The new MMP inhibitor Ro 28-2653 reduces tumor growth and provides a compatible therapeutic alternative for patients with prostate cancer.

Topics: Animals; Antineoplastic Agents, Hormonal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Estramustine; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasms, Hormone-Dependent; Piperazines; Prostatic Neoplasms; Pyrimidines; Rats; Rats, Inbred Strains; Survival Rate; Time Factors; Tumor Cells, Cultured

To demonstrate a synergistic action between high intensity focal ultrasound (HIFU) and combination chemotherapy with paclitaxel and estramustine phosphate (EMP) on a prostate cancer model.. The animal model used in this study was the Copenhagen rat and the tumour model is a Dunning R 3327-AT 2 hormone-independent prostatic adenocarcinoma cell line. Chemotherapy was administered once a week for 4 weeks according to 2 modalities: low-dose with paclitaxel 2 mg/kg/day, 1 day per week and EMP 50 mg/kg/day, 3 days per week; or high-dose with paclitaxel 3 mg/kg/day, 1 day per week and EMP 75 mg/kg/day, 3 days per week. Treatment with HIFU was performed at the second week and only 55% of the tumour volume was treated. The study was conducted on 42 rats divided into 6 arms: Control, HIFU, low-dose paclitaxel-EMP, high-dose paclitaxel-EMP, HIFU + low-dose paclitaxel-EMP and HIFU + high-dose paclitaxel-EMP. Study endpoints were the course of tumour volume and animal survival.. After two weeks of treatment, a statistically significant difference for tumour volume was observed between the various arms of the study (p < 0.0001). The HIFU-chemotherapy arm and, to a lesser degree, the chemotherapy only arm, presented the lowest tumour progression.. The combination of HIFU + paclitaxel-EMP is more effective than treatment with HIFU alone or paclitaxel-EMP alone on growth of the Dunning tumour, right from the first weeks of treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Combined Modality Therapy; Disease Models, Animal; Estramustine; Male; Paclitaxel; Prostatic Neoplasms; Rats; Ultrasonic Therapy

Estramustine (EaM), a carbamate ester of 17beta-estradiol and nor-nitrogen mustard, is a cytotoxic compound with antitumoral effect in malignant glioma in vitro and in vivo . However, knowledge of the pharmacokinetics of EaM in experimental glioma is limited. The objective of this study was therefore to investigate further the distribution of EaM in the BT4C rat glioma model. Assessment of EaM uptake and distribution was performed by quantitative whole-body autoradiography. In addition, the uptake of EaM and its metabolites estromustine (EoM), estradiol, and estrone were analyzed by gas chromatography. EaM was taken up from the circulation and was found to be the main product in glioma tissue. Whole-body autoradiography after [14C]-EaM administration revealed a strong 14C label simultaneously in tumor and normal brain tissue at 0.5 h after drug administration. In tumor tissue, sustained high levels of 14C label were detected at 12 h after drug administration. In contrast to the tumor, radioactivity in normal brain tissue rapidly leveled off, indicating a retention of radioactivity in the tumor. The tumor/brain radioactivity ratio reached a peak of 4.5 at 12 h after drug administration. High levels of 14C label were also found in pulmonary tissue. By gas chromatography, EoM was found to be the main metabolite in plasma. However, EaM reached higher levels in tumor tissue, with the mean tumor/plasma ratio being 11.7 as compared with 2.0 for EoM. Only low plasma levels of the estrogen metabolites were detected. In conclusion, EaM is taken up in the BT4C rat glioma tissue and is retained in the tumor as compared with normal brain tissue and plasma. EaM showed a greater selectivity for tumor tissue, exhibiting a high tumor/plasma ratio as compared with EoM. The distribution pattern after administration of EaM, as evaluated by both whole-body autoradiography and gas chromatography, supports the earlier suggestion that the uptake is related to a protein with EaM-binding characteristics.

Topics: Animals; Antineoplastic Agents, Alkylating; Autoradiography; Brain; Brain Neoplasms; Chromatography, Gas; Disease Models, Animal; Estramustine; Glioma; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Tissue Distribution

Androgen-responsive cells: To determine if testosterone or dihydrotestosterone is the main trophic hormone of prostatic adenocarcinoma, we have treated Dunning R3327H prostatic adenocarcinoma-bearing rats with 6-methylene progesterone, which blocks conversion of testosterone to dihydrotestosterone. Copenhagen-Fisher rats were treated with steroid (20 mg/Kg daily) immediately following implantation of tumor and thereafter for 117 days. There was a 92% inhibition of growth of tumors and a lesser effect upon prostate and seminal vesicles. Tumor-free body weights remained unchanged. Both treated and untreated tumors had equivalent DNA content on a per weight basis. This result supports the thesis that prostatic adenocarcinoma requires dihydrotestosterone for growth. Androgen-insensitive cells: Advanced prostate cancer does not respond to endocrine therapy but is temporarily controlled by the cytotoxic steroid estramustine. The latter shows significant selective binding to prostatic protein. To develop chemotherapeutic agents that will control androgen-insensitive cells and possess improved selectivity for prostatic protein, we have studied a number of steroids for their ability to displace 3H-labeled estramustine from prostatic cytosolic proteins. Surprisingly, a carbamido substituent at the C17 position was found to confer significant binding affinity for prostatic estramustine-binding protein. Extension of this structural characteristic to the estramustine type of molecule is being studied.

Topics: 5-alpha Reductase Inhibitors; Adenocarcinoma; Animals; Carrier Proteins; Disease Models, Animal; Estramustine; Male; Neoplasm Transplantation; Organ Size; Progesterone; Prostate; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Structure-Activity Relationship