Dunning Prostate Cancer Model Research Articles

Metformin protects against diabetes-induced heart injury and dunning prostate cancer model.

In this study, both diabetes and Dunning prostate cancer were induced for the first time in Copenhagen rats in vivo. Thus, the effects of metformin against heart tissue damage of these rats were investigated by biochemical methods. Dunning prostate cancer was induced in Copenhagen rats using high metastatic MAT-LyLu cells. The rats were divided as follows: Control group: only injected with 0.9% NaCl for 14 days; Diabetic group: only injected single dose of streptozotocin (STZ) (65 mg/kg); Cancer group: subcutaneously (s.c) inoculated with 2 x 104 MAT-LyLu cells only; Diabetic + cancer (DC) group: inoculated with 2 x 104 MAT-LyLu cells and STZ injection, Cancer + metformin (CM) group: injected with metformin for 14 days after Mat-LyLu cells application; Diabetic + cancer + metformin (DCM) group: metformin administered for 14 days together with STZ and Mat-LyLu cells. At the end of the experimental period, heart tissues were taken. Reduced glutathione and total antioxidant status levels in heart tissues were decreased, whereas lipid peroxidation, advanced oxidized protein products, nitric oxide, homocysteine, and reactive oxygen species levels, total oxidant status and catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and xanthine oxidase activities increased in the diabetic, cancer and DC groups. Treatment with metformin reversed these effects. In conclusion, the present study shows that metformin has a protective effect against heart tissue damage in STZ-induced diabetic rats with Dunning prostate cancer.

Enhanced inhibitory effect of the matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine and etoposide on the prostate carcinoma in the rat Dunning orthotopic tumor model

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.

Multi-Slice DCE-MRI Data Using P760 Distinguishes Between Metastatic and Non-Metastatic Rodent Prostate Tumors

An intermediate molecular weight contrast agent P760 was used to investigate the ability of multi-slice dynamic contrast-enhanced MRI (DCE-MRI) to distinguish metastatic from non-metastatic rodent prostate tumors. Non-metastatic AT2.1 and metastatic AT3.1 prostate tumors originally derived from the Dunning prostate cancer model were implanted on the hind leg of Copenhagen rats. Multi-sliced DCE-MRI data were acquired on a SIGNA 1.5 T scanner and analyzed using a recently developed empirical mathematical model. The P760 multi-slice DCE-MRI data in combination with the empirical mathematical model successfully distinguished between metastatic and non-metastatic rodent prostate tumors. Specifically, fitting the data with the empirical model showed that metastatic tumors had significantly faster contrast media uptake (p<0.001) and slower washout rates (p<0.01) than non-metastatic tumors.

Thrombospondins, metallo proteases and thrombospondin receptors messenger RNA and protein expression in different tumour sublines of the Dunning prostate cancer model

Thrombospondin is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. TSP interacts with a number of proteases and receptors and in this way inhibits stimulation of angiogenesis. An earlier study showed that thrombospondin is expressed in benign prostatic hyperplasia (BPH) and high-grade prostatic intraepithelial neoplasia (PIN) but is absent in prostate cancer. The present study was therefore designed to evaluate the expression of thrombospondin 1 and 2 (TSP-1, TSP-2), TSP receptors CD36 and CD47, and matrix-metalloproteases 2 and 9 (MMP-, MMP-9) in a rat prostate cancer model. By using immunohistochemistry, Western blot, and real-time PCR the expression patterns of TSP-1, TSP-2, CD36, CD47, MMP-2, and MMP-9 were investigated in normal rat prostate tissue and five malignant Dunning sublines tissue. TSP-1 mRNA levels were decreased in all tumours compared with normal prostate. However, there was no difference in expression of TSP-2 and CD36 mRNA in these samples. MMP-2 was increased with malignancy, but no expression of MMP-9 was seen. The CD47 receptor did slightly increase with malignancy except for H3327. The results showed that thrombospondin is expressed in normal prostate but not in prostate tumours in a rat model. Simultaneously, MMP-2 expression increases with malignancy.

Lycopene and vitamin E interfere with autocrine/paracrine loops in the Dunning prostate cancer model.

Epidemiological studies have consistently associated high intakes of lycopene or vitamin E with a reduced prostate cancer risk. Both compounds were tested in the MatLyLu Dunning prostate cancer model to gain insight into the in vivo action of lycopene and vitamin E. Supplementation for 4 weeks with 200 ppm lycopene, 540 ppm vitamin E, or both led to plasma levels comparable with those in humans. Both compounds also accumulated in tumor tissue. Macroscopic evaluation of the tumors by magnetic resonance imaging showed a significant increase in necrotic area in the vitamin E and the lycopene treatment groups. Microarray analysis of tumor tissues revealed that both compounds regulated local gene expression. Vitamin E reduced androgen signaling without affecting androgen metabolism. Lycopene interfered with local testosterone activation by down-regulating 5-alpha-reductase and consequently reduced steroid target genes expression (cystatin-related protein 1 and 2, prostatic spermine binding protein, prostatic steroid binding protein C1, C2 and C3 chain, probasin). In addition, lycopene down-regulated prostatic IGF-I and IL-6 expression. Based on these findings, we suggest that lycopene and vitamin E contribute to the reduction of prostate cancer by interfering with internal autocrine or paracrine loops of sex steroid hormone and growth factor activation/synthesis and signaling in the prostate.

Suppression of Tumor Recurrence and Metastasis by a Combination of the PHSCN Sequence and the Antiangiogenic Compound Tetrathiomolybdate in Prostate Carcinoma

Plasma fibronectin-mediated invasion of human DU145 prostate cancer cell line was efficaciously inhibited in a rat tumor model by treatment with Ac-PHSCN-NH2 peptide. Invasion of DU145 cells was stimulated by the PHSCN sequence of plasma fibronectin. However, PHSCN acts as a competitive inhibitor of PHSRNmediated invasion. In the current study, we determined whether PHSCN could inhibit the recurrence and metastasis of DU145 tumors after excision of the primary tumor in an athymic nude mouse model. We demonstrated that mice treated thrice weekly with intravenous Ac-PHSCN-NHZ peptide survived tumor-free for more than 30 weeks post-primary tumor excision, whereas their untreated counterparts succumbed to recurrence and/or metastatic disease in significantly less time. Because of the universal requirement for angiogenesis in solid tumor growth, we tested the efficacy of copper deficiency induced by tetrathiomolybdate. (TM) to retard tumor growth in the Dunning prostate cancer model. Significant reduction in size of the primary tumor was observed in mice rendered copper deficient. We sought to reduce tumor growth at the primary and metastatic sites by combining the anti-invasion Ac-PHSCN-NH2 peptide with TM. Improved survival, fewer metastatic lesions, excellent tolerability were observed with the combination therapy.

Gene therapy for human prostate cancer. Translational research in the hormone refractory dunning prostate cancer model

Background. Genetically engineered tumor vaccines are feasible for clinical trials in human prostate cancer, and Phase I testing has been approved. The Dunning rat prostate cancer model provides an opportunity for translational research to rationally design Phase II clinical studies testing efficacy. Methods. The Dunning R3327 MAT-LyLu subline was transduced with the retroviral vector MFG carrying the cytokine gene for human granulocyte-macrophage colony-stimulating factor (GM-CSF). Varying secretion rates of human GM-CSF were generated and tumor cell vaccines were formulated, consisting of 5 X 10 6 lethally irradiated transduced cells. The vaccines were placed at a subcutaneous site opposite preestablished tumor of 1 X 10 4 cells implanted 3 days earlier in Copenhagen rats. Trials were masked, randomized, and conducted over 6-week intervals using different treatment schedules, vaccine number, and varying doses of human GM-CSF secretion as well as appropriate controls. Results. Thirty percent of rats with long term follow-up can be cured of preestablished tumor burdens with human GM-CSF transduced tumor vaccines secreting greater than 140 ng/10 6 cells/24 hours of human GM-CSF. All studies evaluating more than one vaccine over a wide range of human GM-CSF secretion rates show significant delays in tumor appearance and progression. One vaccination is not curative. Vaccination with GM-CSF transduced tumor vaccines increased disease free survival and slowed tumor progression over animals vaccinated with irradiated tumor cells admixed with either soluble GM-CSF or with a nonspecific immune adjuvant (Corynebacterium parvum). The ability to cure animals and delay progression appears related to total duration of human GM-CSF secretion at the subcutaneous site. Systemic human GM-CSF could be detected in the serum of rats for at least 6 days after vaccination. Conclusions. These data have implications for the design of gene therapy trials in prostate cancer. Small androgen independent tumor burdens such as volumes seen in the adjuvant setting can be cured. Multiple vaccinations with adequate human GM-CSF secretion are required. At higher human GM-CSF secretion rates, systemic levels may be achievable, and patients should be evaluated closely for toxicity to and the pharmacokinetics of GM-CSF. Concer 1995 ; 75 :2013-20.

Misonidazole as a Chemosensitizer in the Treatment of the Dunning Prostate Cancer Model

Utilizing a Dunning prostate tumor model, we investigated the ability of misonidazole, a compound with known radio sensitizing properties, to act as a chemosensitizer when administered in combination with the alkylating agent cyclophosphamide. This combination caused a decrease in tumor growth rate when compared to the growth of the tumor in animals receiving cyclophosphamide alone. However, only at toxic levels was this decrease statistically significant (p > 0.01).