The disintegrin contortrostatin in combination with docetaxel is a potent inhibitor of prostate cancer in vitro and in vivo.
BACKGROUND
There are few available treatments for hormone refractory prostate cancer. Through the inhibition of integrins, contortrostatin (CN) effects tumor cell growth directly as well as through the inhibition of angiogenesis. The effect of CN in combination with docetaxel on prostate cancer cell lines in vitro and in vivo is evaluated in the present study.


METHODS
FACS analysis of integrin expression, assessment of CN and docetaxel exposure on viability of plated cancer cells, and scratch test migration analysis were performed on PC-3 prostate cancer cells. CN and docetaxel inhibition of both PC-3 and CWR-22 prostate cancer cell lines were evaluated in a mouse xenograft bone model. Angiogenic activity in tumors were assessed using IHC with antibodies to CD31.


RESULTS
Cell culture experiments indicate that the combination of docetaxel and CN inhibits growth in an additive fashion. FACS analysis of PC-3 cells shows expression of alpha5beta1 and alphavbeta5 integrins, but little expression of the alphavbeta3. CN showed complete inhibition of PC-3 migration in cultures grown on matrigel plates. In mice xenograft bone models, CN with docetaxel showed increased inhibition of both PC-3 and CWR-22 derived tumors. Analysis of treated xenograft tumors showed significantly decreased expression of CD31 indicating suppression of angiogenesis.
Lin
Edwin
E
Department of Internal Medicine, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA.
Wang
Qingcai
Q
Swenson
Stephen
S
Jadvar
Hossein
H
Groshen
Susan
S
Ye
Wei
W
Markland
Francis S
FS
Pinski
Jacek
J
D000818:Animals; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019483:Disintegrins / Q000627:therapeutic use*; D000077143:Docetaxel; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects
D019483:Disintegrins; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; C403494:contortrostatin; D000077143:Docetaxel