Die Bedeutung der Lektinblockade für die Metastasenprophylaxe

Author(s): Beuth, J., Ko, H., Pichlmaier, H., Said, S., Oette, K., Uhlenbruck, G.

Abstract: After the discovery of vertebrate liver lecterns by Ashwell and Morell in 1974 we have advanced the hypothesis that organcharacteristic lectins may act as acceptors of malignant tumor cells in the metastatic process by interacting with tumor-associated carbohydrates on the surface of metastatic tumor cells. Because of the D-galactose (Gal)-specificity of liver lectins (= hepatic binding proteins, HBPS) we further suggested that lectin blockade (with Gal-containing receptor analogues) or dysfunction may inhibit the metastatic spread into the liver. Diverse experimental approaches confirmed these postulations and suggested therapeutical relevance for clinical oncology.Adhesion and inhibition experiments with liver and lung parenchymal cells and tumor cells indicated that lectins or lectinlike adhesion molecules with D-galactose specificity (hepatocytes) and L-fucose specificity (pulmonary cells) apparently mediate specific cell-cell interactions. In vivo, repeated administration of lectinblocking glycoconjugates significantly inhibited the settling of metastatic tumor cells in murine livers and lungs. Nonspecific glycoconjugates did not influence the metastatic spread into target organs. Therefore, when organ-characteristic lectins were blockeed with competitive receptor analogues, tumor colonization of liver and lung be significantly reduced. Acute (hepatitis) and chronic (cirrhosis) liver injuries were experimentally induced in mice by administation of D-galactosamine and carbon-tetrachloride (CCI 4) to damage organ-characteristic lectins. In both experimental liver diseases the incidence of hepatic tumor colonization was significantly reduced, as compared to non-treated control mice, thus, it seems that (besides blocking with specific glycoconjugates) dysfunction or loss of organ-characteristic lectins prevented metastatic liver colonization. Histochemical stainings of liver sections from D-galactosamine or CCI 4-treated mice with appropriate galactose-containing (neo)glycoproteins confirmed this hypothesis since the lectin-dependent binding was greatly reduced as compared to sections from non-treated mice.Recently, a prospective randomized clinical study was initiated tot patients suffering from colorectal cancer. To inhibit the (peri)operative spread of tumor cells into the liver of those patients, a 4 days Gal-infusion (1.6 gram/kg body weight/24 hrs) was preoperatively (1 hr) started as to block the Gal-specific liver lectins and to inhibit the metastatic settling of tumor cells in the liver. According to preceeding experimentat studies this schedule of treatment proved to be optimal for the prevention of organ (liver) metastasis. After a mean follow up of 22 month, 145 patients are now randomized in this clinical study in Cologne, FRG. So far, there is no obvious difference in control group (treated with standard infusion therapy) and therapy group (treated with Gal as described) concerning age and sex of patients, localization and staging of tumor, duration and side effects of operation. Furtheron, Gal-infusion dependent side effects were negligible, however, the incidence of liver metastases is definitely lower in the therapy group as compared to the control group. At the moment, the number of patients and the mean follow up time still are not sufficient to evaluate this study statistically, however, a positive trend may be appreciated.

Keyword(s): Metastasenprophylaxe

Zurück | Weiter