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.
OBJECTIVE
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).


METHODS
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.


RESULTS
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%.


CONCLUSIONS
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.
Abramjuk
Claudia
C
Department of Urology, University Hospital Charité, Humboldt University, Schumannstrasse 20/21, 10098, Berlin, Germany.
Lein
Michael
M
Rothaug
Winfried
W
Krell
Hans-Willi
HW
Loening
Stefan A
SA
Jung
Klaus
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D004961:Estramustine / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000008:administration & dosage
D010879:Piperazines; D011743:Pyrimidines; C453902:Ro 28-2653; D019714:Tissue Inhibitor of Metalloproteinases; D004961:Estramustine; D005047:Etoposide