ro-28-2653 and Body-Weight

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 effect of Ro 28-2653, a synthetic matrix metalloproteinase (MMP) inhibitor, on adipose tissue development was studied in mice kept on a high fat diet (HFD). Five-week-old male wild-type (C57Bl/6J) mice were fed the HFD (42% kcal as fat, 20.1 kJ/g) and received daily p.o. instillations of inhibitor (30 mg/kg) or vehicle. After 15 weeks of the HFD, the body weight gain was lower in the inhibitor-treated group (7.4 +/- 0.88 g versus 10 +/- 1.4 g) whereas the weights of the isolated subcutaneous (SC) or gonadal (GON) fat deposits were 10-15% lower. The number of adipocytes in adipose tissues of the inhibitor-treated mice was somewhat higher (10-17%) but their diameter was smaller (about 10%). In situ zymography showed reduced gelatinolytic activity in SC (about 2.7-fold) and GON (1.4-fold) adipose tissue of inhibitor-treated mice, whereas their fibrillar collagen content was higher (1.5- and 4.7-fold, respectively). In both SC and GON adipose tissues of inhibitor-treated mice, MMP-2 (gelatinase A) and MMP-14 (membrane type-1 MMP) were 2- to 3-fold upregulated, whereas MMP-9 (gelatinase B) mRNA levels were not affected. Thus, in this in vivo model partial inhibition of gelatinolytic activity is associated with moderate effects on adipose tissue development and cellularity. Possibly, enhanced MMP expression to some extent counteracts the in vivo effect of the inhibitor in adipose tissue.

Topics: Adipose Tissue; Animal Feed; Animals; Body Weight; Dietary Fats; DNA Primers; Enzyme Inhibitors; Gene Expression Regulation; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Obesity; Piperazines; Pyrimidines; RNA, Messenger; Time Factors