INHIBITORY EFFECTS OF TUMOR INVASION-INHIBITING FACTOR-2 AND ITS CONJUGATE ON DISSEMINATING TUMOR-CELLS

Tumor invasion-inhibiting factor 2 (IIF-2) is a polypeptide of 21 amin o acids which binds to the surface of tumor cells and inhibits experim ental invasion in vitro. An albumin conjugate of IIF-2 was used to exa mine its potential as an antimetastatic compound. The conjugate inhibi ts in vivo lung metastasis of various highly metastatic tumor cells, i ncluding murine melanoma, colon adenocarcinoma, squamous cell carcinom a, forestomach carcinoma, and human fibrosarcoma. In addition to the a nti-lung metastasis activity of this compound, it also showed the inhi bitory effects on Liver and spleen metastasis of murine T-lymphoma cel ls. A single administration of the conjugate with melanoma cells resul ted in prolonged survival times, and their lung colonization was also inhibited when the conjugate was administrated i.v. at times ranging f rom 6 h before to 1 h after tumor cell inoculation. Similarly i.p. adm inistration 1 h prior to melanoma cell. injection suppressed lung colo nization. Pharmacokinetic analysis revealed that the conjugate was mor e stable than IIF-2 peptide atone. Approximately 10% of the conjugate remained circulating 2 h postinjection and persisted 20 h without degr adation, compared with rapid clearing of the unconjugated IIF-2 peptid e within 5 min. Furthermore, spontane- ons lung metastasis of murine m elanoma and colon adenocarcinoma cell was inhibited by successive i.p. administration of the conjugate before the removal of the primary sit e, with no effect on primary tumor growth. The conjugate significantly reduced tumor cell arrest in the lung and both the IIF-2 peptide and its conjugate demonstrated potent inhibition of basal as well as cytok ine-induced-stimulated tumor cell motility. These results suggest that one mode of IIF-2 action may be inhibition of the extravasation of me tastasizing cells which have arrested in a target organ, and that the IIF-2-albumin conjugate may be a patent antimetastatic substance with utility in the prevention of artificial seeding of tumor cells during surgical removal of the primary lesions as well as inhibiting metastas is from established metastases.