Correlation between antitumor activity of protein A and in vivo formation of defined high molecular weight complexes with immunoglobulin G in BALB/c mice.
The purpose of this study was to test the hypothesis that antitumor activity of staphylococcal protein A (SpA) is related to the composition of complexes formed in vivo with IgG. BALB/c mice were inoculated intradermally with 10(6) Meth A fibrosarcoma cells on day 0 and treated i.v. on days 3 and 7 with between 1 and 405 micrograms of SpA. The 45- and 15-micrograms doses significantly inhibited tumor growth and enhanced survival time compared to saline controls in four of four and two of four experiments, respectively. Sucrose gradient ultracentrifugation was used to show that serum from tumor-bearing or normal mice given 45 or 15 micrograms of 125I-labeled SpA contained only high molecular weight [(IgG)2SpA]2 complexes for up to 24 h after injection, whereas serum from mice given higher ineffective doses (135 and 405 micrograms) contained low molecular weight (IgG)(SpA) complexes over the first 1-4 h. Serum from mice undergoing successful therapy with 45 micrograms of unlabeled SpA also contained only [(IgG)2SpA]2 complexes. In contrast, when mice with large tumors (120-150 mm2) were treated on days 16 and 20, only the 135- and 405-micrograms doses significantly inhibited further tumor growth. Serum from mice with 16-day tumors contained only [(IgG)2SpA]2 complexes even after 5 min and when 135 or 405 micrograms of 125I-SpA was given. This result is consistent with significantly higher (2.7-3.4-fold, P less than 0.0001) levels of total and SpA-reactive IgG in serum from these mice compared to normal mice or mice with 3-day tumors. Our results demonstrate a correlation between antitumor activity of SpA and in vivo formation of [(IgG)2SpA]2 complexes in an established animal model, and help to define the mechanism of SpA action at the molecular level.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism*; D007457:Iodine Radioisotopes; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D013205:Staphylococcal Protein A / Q000378:metabolism / Q000494:pharmacology*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D013205:Staphylococcal Protein A