NE-AUA 2006 Annual Meeting, September 28 - 30, 2006, The Westin Hotel & Rhode Island Convention Center Providence, Rhode Island
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Degradation of Matrix Fibronectin: Does it Affect Attachment of BCG to the Bladder Mucosa?
Imbesat Daudi, MD, PhD.
Aroostook Urology, Presque Isle, ME,

Background: Adjuvant intravesical therapy is more effective in the treatment of Carcinoma in Situ and Transitional Cell Carcinoma of urothelium compared to Transurethral Resection (TURBT) alone or TURBT with other adjuvant chemotherapy such as Adriamycin or thiotepa. Still five year tumor free response is only 70% and its application is associated with significant lower urinary tract symptoms. Matrix fibronectin is 440 kd protein which is believed to be essential in its intact form in the attachment of BCG to the bladder mucosa. Fibronectin can be degraded by proteases released from inflammatory macrophages and polymorphonuclear leukocytes (PMNL).
Methods: We examined the ability of elicited macrophages and PMNL harvested from the peritoneal cavity of rats to fragment fibronectin (Fn) bound to the denatured collagen (gelatin). Gelatin coated microtiter plates were supplemented with rat 125 I plasma Fn purified by affinity chromatography. Opsonized zymosan stimulated PMNL and macrophages were added to the plasma Fn-gelatin coated surface and proteolysis of bound 125 I-Fn was quantified by the release of 125 I Fn in the media.
Results: After two hours of incubation, stimulated macrophage and PMNL both released more than three times more 125 I-Fn antigens than control wells (without cells) and twice as much as non-stomulated cells. Release of of the 125 I fn fragments was inhibited by N-p-tosyl-L-lysin cloromethyl Ketone (TLCK), a trypsin specific inhibitor; but not by methoxysuccinal-alnine-proline-valine chlormethyl ketone (AAPVCK), a leukocyte elastase specific inhibitor. This is in contrast to PMNL which degrades Fn by leukocyte elastase, a process blocked by AAPVCK.
Conclusions: Thus, Fn complexed with denatured collagen is susceptible to proteolysis by activated macrophage and PMNL which has the potential to block the formation of Fn-BCG complex and thereby influence the efficiency of BCG treatment. It is also a potential pathway to influence its side effects on the lower urinary tract.


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