Intravesical bacille Calmette-Guérin induces the antiangiogenic chemokine interferon-inducible protein 10.
OBJECTIVE
Intravesical bacille Calmette-Guérin (BCG) induces a variety of cytokines into the urine of patients with superficial transitional cell carcinoma (TCC) of the bladder. Recent data have shown that some cytokines have antiangiogenic activity. We sought to determine whether the potently antiangiogenic chemokine interferon-inducible protein 10 (IP-10) and its inducing antiangiogenic cytokines, interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), are increased during intravesical BCG immunotherapy of bladder TCC.


METHODS
Voided urine samples were collected sequentially from 8 patients before and after each weekly intravesical BCG treatment and from 4 patients receiving maintenance BCG treatments. The urinary output of IP-10, IFN-gamma, and IL-12 over 12 post-treatment hours was assessed by enzyme-linked immunosorbent assay. In vitro BCG and cytokine stimulations of human TCC and primary endothelial cell lines were also performed, and their supernatants were studied for IP-10.


RESULTS
In all cases after intravesical BCG, patient urine was found to contain significant elevations of IP-10. Urinary IFN-gamma and IL-12 levels also increased in similar patterns after intravesical BCG. The peak weekly cytokine response per patient usually occurred between the fourth and sixth treatment for IFN-gamma and IP-10, but was less predictable for IL-12. Human TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or interferon stimulation in vitro.


CONCLUSIONS
Our small series demonstrates that IP-10 and its inducing cytokines are elevated in response to intravesical BCG. These data suggest that, in addition to a cellular immune response, BCG may induce a cytokine-mediated antiangiogenic environment that aids in inhibiting future tumor growth and progression.
Department of Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
D P
DP
Poppas
C P
CP
Pavlovich
J
J
Folkman
E E
EE
Voest
X
X
Chen
A D
AD
Luster
M A
MA
O'Donnell
D000283:Administration, Intravesical; D001500:BCG Vaccine / Q000008:administration & dosage*; D002295:Carcinoma, Transitional Cell / Q000628:therapy* / Q000652:urine; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology* / Q000652:urine; D018664:Interleukin-12 / Q000502:physiology / Q000652:urine; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000628:therapy* / Q000652:urine
D001500:BCG Vaccine; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D018664:Interleukin-12; D007371:Interferon-gamma