Efficacy of antiangiogenic therapy with TNP-470 in superficial and invasive bladder cancer models in mice.
OBJECTIVE
To evaluate the efficacy of antiangiogenic therapy with O-(chloracetyl-carbamoyl) fumagillol (TNP-470) in a superficial and an invasive bladder cancer model in mice. The control of recurrent superficial and metastatic bladder cancer constitutes a major problem in urologic practice. Although the established therapies for these cases (immunotherapy, chemotherapy, and radiation therapy) have improved during the previous decades, further improvement and the reduction of existing side effects are needed. The inhibition of angiogenesis represents a new concept in cancer therapy.


METHODS
We evaluated the in vitro effect of TNP-470 on the proliferation of bovine capillary endothelial cells (BCE), the superficial transitional cell carcinoma (TCC) cell line (KK-47), and the invasive TCC cell line (MGH-U1). To evaluate the in vivo effect of TNP-470 on the growth of advanced TCCs, both cell lines were injected subcutaneously into SCID mice. When tumors grew to a size of 100 to 200 mm(3), therapy either with TNP-470 or phosphate-buffered saline was initiated.


RESULTS
TNP-470 strongly inhibited endothelial cell proliferation in vitro. The in vitro proliferation of both bladder carcinoma cell lines was also inhibited by TNP-470. However, the doses inhibitory to bladder carcinoma cells were 100-fold higher than the doses that were effective in the inhibition of endothelial cell proliferation. In vivo, TNP-470 significantly inhibited the growth of advanced KK-47 (67%) and MGH-U1 (68%) tumors in SCID mice.


CONCLUSIONS
Our results indicate that antiangiogenic therapy with TNP-470 is equally effective in advanced superficial and invasive bladder carcinoma models in mice. When our results are taken together with the reports of other laboratories, TNP-470 appears to be a promising candidate as a tumor suppressor in superficial and invasive bladder cancer.
Beecken
W D
WD
Department of Surgery, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
Fernandez
A
A
Panigrahy
D
D
Achilles
E G
EG
Kisker
O
O
Flynn
E
E
Joussen
A M
AM
Folkman
J
J
Shing
Y
Y
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000188:drug therapy*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D004354:Drug Screening Assays, Antitumor; D005260:Female; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol