Intra-tumoral application of a heregulin-exotoxin-A fusion protein causes rapid tumor regression without adverse systemic or local effects

Abstract

Tumor toxins are recombinant, bifunctional proteins which comprise a tumor-cell-specific recognition domain and an enzymatic toxin domain. We have evaluated the in vivo effects of a tumor toxin that specifically recognizes the erbB-3 and erbB-4 receptors (HRG beta 1-ETA). High doses of HRG beta 1-ETA administered systemically (intracardially or intraperitoneally) caused acute liver necrosis and were lethal. The same dose of tumor toxins applied subcutaneously had no detectable histopathological effects. The anti-tumor activity of HRG beta 1-ETA was tested in nude mice with xenografts of a human breast tumor, MAXF1162. The MAXF1162 tumor grew rapidly upon s.c. implantation. Intra-tumoral application of HRG beta 1-ETA (7 times 5 micrograms over a period of 21 days) induced complete regression of tumors. At the time the treatment was terminated, no tumor cells were detectable microscopically. Evaluation of the liver of treated animals revealed no significant toxicity in the effective dose range. These experiments indicate that tumor toxins can become valuable for local tumor treatment and for reduction of tumor burden.