In vivo effects of recombinant human lymphotoxin on human medulloblastoma xenograft: Enhancement of antitumor activity of etoposide

The authors investigated the antitumor activities of rHuLT alone and in combination with etoposide on human medulloblastoma xenografts growing subcutaneously in nude mice. Intravenous administration of rHuLT (1.0×10⁵U/kg, 5.0×10⁵U/kg, 2.5×10⁶U/kg, three times a week for three weeks) suppressed medulloblastoma growth depending on the dose. However, the highest dosage caused serious side effects. Combining rHuLT (intravenously, 5.0×10⁵U/kg, three times a week for three weeks) with etoposide (intraperitoneally, 20mg/kg, once a week for three weeks) increased the antitumor activity without causing serious toxicity. Microscopically, tumor specimen showed thrombosed tumor vessels and massive necrosis 3 weeks after rHuLT treatment. Ultrastructural examination revealed that 120 minutes after the administration of rHuLT alone, disruption of interendothelial junctions was evident, and that the endothelial cells were destroyed at 240 minutes.Concentration of etoposide in tumor tissue peaked 30 minutes after intraperitoneal administration, and then decreased with time. When etoposide was administered in combination with rHuLT, the concentration of etoposide in tumor tissue after 60 to 240 minutes was significantly higher than when etoposide was given alone, and the area under the concentrationversus time curve was also greater for the tumors of mice with combination treatment.The findings suggest that the proper combination of rHuLT and etoposide may have synergistic antitumor activities. Histological changes suggest that increased concentrations of etoposide within the tumor after combination therapy may occur due to increased vascular permeability and/or decreased etoposide clearance which is the result of blood stasis in the tumor vasculature.Abbreviations AUC area under the concentration versus time curve - LT lymphotoxin - rHuLT recombinant human lymphotoxin - rHuTNF recombinant human tumor necrosis factor - TNF tumor necrosis factor