Towards an Understanding of the Mode of Action of Bacillus Calmette-Guérin-Therapy in Bladder Cancer Treatment, Especially with Regard to the Role of Fibronectin

Abstract

Summary:The interaction between Bacillus Calmette-Guerin (BCG) and the host was investigated after repeated intravesicular BCG-therapy for superficial bladder cancer. Studies were performed on (a) the local reaction in the bladder, (b) the systemic reaction, and (c) short and long term interactions in both the bladder and the serum/plasma.The analytes measured included anti-BCG IgA and IgG, fibronectin, lactoferrin, elastase-oci-proteinase inhibitor, myeloperoxidase and oc 2 -proteinase inhibitor. All analytes, with the exception of oc 2 -proteinase inhibitor, were measured in both serum/plasma and urine.An additional group of 94 patients undergoing bronchoalveolar lavage was used for comparison with other diseases affecting mucous membranes. In vitro studies on human bladder in culture were also carried out to study the relationship between BCG, elastase and fibronectin.The results revealed a normal defence reaction, in which IgA and IgG antibodies specific to BCG were produced by the host. Maximal concentrations of all analytes in urine were found about 4 h after BCG instillation.Immunoglobulins, soluble fibronectin, and granulocyte markers all appeared in urine after instillation and all showed a similar time course. The in vitro study showed the synergistic effect of elastase and BCG in stimulating the host defence reaction. The relationship between BCG and fibronectin can be seen as fortuitous but not indicative of the efficacy of BCG-therapy in patients with superficial bladder cancer. Introduction(2-4), the necessity for the presence of a fibrin clot (3, 5), the saturation of BCG receptors with soluble Although post-operative intravesicular treatment of monomeric fibronectin (6), and the mediation of Tsuperficial bladder cancer with Bacillus Calmette-lymphocytes (7). Studies in these laboratories over the Guerin (BCG) has been carried out for some 15 years past four years have revealed further physiological (1) the exact mode of action of this therapy is still factors which may contribute to the action of BCG not known. Many theories have been postulated, in-in promoting an "anti-tumour" reaction in cases opeluding the interaction between BCG and fibronectin erated for superficial bladder cancer.

Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer

“…Our present data suggest that early IL-8 induction is important for subsequent development of an immune response and thus may be, indirectly, involved in the antitumor efficacy of BCG therapy. Possibly IL-8 acts by attracting neutrophils to the bladder, after which these activated cells facilitate BCG invasion and/or leukocyte infiltration by proteolytic enzyme production [14]. In addition, apart from the traditional involvement in inflammatory response, these neutropils could significantly influence the immune and antitumor response by the release of cytokines [4].…”

“…Since a rapid influx of neutrophils after BCG instillation is observed in the urine of bladder cancer patients [5], we considered that IL-8, produced by urothelial cells in response to BCG exposure, could be responsible for the attraction of these neutrophils. Locally attracted and activated neutrophils can produce cytokines and proteolytic enzymes [4,14], which could possibly result in facilitated bladder wall infiltration by leukocytes and/or BCG and enhancement of the immune response. In this manner IL-8 production by urothelial cells might be important for the subsequent development of an immune response against BCG and associated clinical efficacy.…”

Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice

“…In fact, infiltration of T cells is not observed when heat-killed BCG is instilled into mouse bladders 7 , suggesting that heat-killed BCG cannot replace live BCG to treat BC patients. The systemic immune reaction after the intravesical instillation of BCG is less well understood, although previous studies have shown that cellular and humoral systemic responses could have a role in or be used as markers of the efficacy of BCG therapy 7 , 10 .…”

Optimierung des orthotopen murinen Harnblasenkarzinom-Modells und Einsatz zur Untersuchung der intravesikalen Bacillus Calmette-Guérin Immuntherapie

“…De Boer u. a. zeigten einen massiven Anstieg von neutrophilen Granulozyten im Urin von Patienten, mit einem Maximum am Tage der BCG-Instillation und an den folgenden zwei Tagen [9]. Die Freisetzung von Granulozyten assoziierten Enzymen, wie Myeloperoxidase, Collagenase, Elastase und Lactoferrin [10] konnte ebenfalls nachgewiesen werden und wurde als eine mögliche Ursache der BCG-induzierten Nebenwirkungen gesehen [11]. Aus diesem Grunde schlossen wir, dass die lokalen BCG-induzier-ten Nebenwirkungen überwiegend durch Granulozyten hervorgerufen werden.…”