Matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine: tumor-reducing effects on hormone-sensitive prostate cancer in rats.

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.

Effect of augmentation cystoplasty on bone metabolism in chronic uremic rats.

PURPOSE: We examined the impact of urinary diversion using several types of intestinal segments on the bone metabolism of growing rats with renal insufficiency. MATERIALS AND METHODS: A total of 110, 8-week-old Sprague-Dawley rats underwent 2-stage subtotal nephrectomy by removal of 5/6 of the renal mass or sham operation. Except for a uremic control group all uremic rats underwent enterocystoplasty using stomach, ileum or colon. An additional group with colic augmentation received the bisphosphonate ibandronate. Bone mineral density of the tibia and lumbar spine, serum analysis and urinary excretion of the bone resorption marker deoxypyridinoline were determined monthly for 12 weeks. At study termination bone ash weight, bone mineral analysis and serum osteotropic hormone levels were determined. RESULTS: All groups undergoing subtotal nephrectomy had a decreased endogenous creatinine clearance of approximately 30%. The lowest gains in tibial and lumbar spine bone mineral density were observed in animals undergoing ileocystoplasty. Femoral calcium content was significantly decreased in uremic ileocystoplasty rats compared with uremic controls. These changes were not induced by alterations in serum pH, nor were they associated with accelerated bone resorption as assessed by deoxypyridinoline. Ibandronate prevented changes related to bone resorption and increased bone mass. CONCLUSIONS: Our results suggest that cystoplasty using ileum segments can aggravate renal bone disease in growing rats with mild uremia. Since the acid-base state was unchanged, other properties of the interposed ileum segment must be responsible for the negative effect on bone metabolism.

The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model.

The therapeutic efficacy of synthetic inhibitors of matrix-metalloproteinases (MMPs) in various cancers has been demonstrated. A novel inhibitor, Ro 28-2653, with high selectivity for MMP2, MMP9 and membrane type 1-MMP was evaluated in an orthotopic prostate cancer rat model. Efficacy was determined by recording tumor growth and survival endpoints. Prostate cancer was induced by inoculating R3327 Dunning tumor cells (MatLyLu) into the ventral lobe of the prostates of 148 Copenhagen rats. Daily oral treatment with Ro 28-2653 (10-300 mg/kg per day) was started on day 1 or on day 6 after tumor cell injection. Animals were sacrificed on day 20 for determination of tumor weights. For survival studies, rats received daily oral Ro 28-2653 (100 mg/kg per day) or vehicle for up to 30 days. Tumor induction was successful in 100% of the animals. Ro 28-2653 reproducibly reduced the tumor weights by up to 90% in a dose-dependent manner. In addition, an inhibitory effect in rats with established tumors (treatment start at day 6) was shown. A significantly prolonged survival of Ro 28-2653-treated rats was also demonstrated. Selective inhibition of MMP activity is a novel therapeutic approach, which bears promise for studies in patients with prostate cancer.