CVS-3983, a selective matriptase inhibitor, suppresses the growth of androgen independent prostate tumor xenografts.
BACKGROUND
Matriptase, a type-II transmembrane serine protease, is expressed by cancers of epithelial origin including breast, colon, and prostate carcinomas and has been implicated in tumor growth and progression. We studied the effects of CVS-3983, a selective small molecule matriptase inhibitor, on the growth of the androgen independent (AI) CWR22R and CWRSA6 human prostate cancer xenograft models.


METHODS
CVS-3983 was administered i.p. twice-daily 7-days per week for 2-3 weeks to mice with established tumors. Measurements of tumor volume were made twice weekly. The effect of CVS-3983 on CWR22RV1 cell invasion through a reconstituted basement membrane matrix of proteins was also evaluated. Matriptase expression across the tumor lines was assessed by RT-PCR and Western blotting.


RESULTS
CVS-3983 inhibited final mean tumor volume by 65.5% (n = 10, P = 0.0002) in the CWR22R model and by 56.2% (n = 8, P = 0.0017) in the CWRSA6 tumor model compared with vehicle-treated tumors. CVS-3983 did not inhibit the proliferation of CWR22RV1 cells in vitro; however, the small molecule did significantly reduce by 30.2% the invasion of these cells in vitro through a reconstituted basement membrane matrix. Molecular analysis of the xenograft tumors demonstrated high expression levels of matriptase at the RNA and protein levels, which were not affected by CVS-3983 treatment.


CONCLUSIONS
These results identify CVS-3983 as a potent inhibitor of AI prostate cancer cell invasion in vitro and established xenograft tumor growth in vivo.
Galkin
Anna V
AV
Cedars-Sinai Louis Warschaw Prostate Cancer Center, Los Angeles, California 90045, USA.
Mullen
Lynne
L
Fox
William D
WD
Brown
Jason
J
Duncan
David
D
Moreno
Ofir
O
Madison
Edwin L
EL
Agus
David B
DB
D000728:Androgens / Q000378:metabolism; D000818:Animals; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; C493012:CVS-3983; D008565:Membrane Proteins; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C485595:matriptase; C118992:St14 protein, mouse