Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCNsequence in prostate carcinoma

Using naturally serum-free SU-ECM basement membranes as invasion substrates showed that plasma fibronectin was necessary to stimulate invasion by DU 1 45 human and metastatic MATLyLu (MLL) rat prostate carcinoma cells. This ac tivity mapped to the PHSRN sequence, which induced invasion through alpha 5 beta 1 integrin, PHSCN, a competitive inhibitor, blocked both PHSRN- and s erum-induced invasion. Acetylated, amidated PHSCN (Ac-PHSCN-NH2) was 30-fol d more potent; however, AcHSPNC-NH2 was inactive. Rats receiving injections s.c. with 100,000 MLL cells were treated systemically by i.v. injection th ree times weekly with 1 mg of either Ac-PHSCN-NH2 or Ac-HSPNC-NH2 beginning 24 h later, three times weekly with 1 mg of Ac-PHSCN-NH2 beginning only af ter surgery to remove large (2 cm) MLL tumors, or were left untreated. MLL tumors grew rapidly in Ac-HSPNC-NH2-treated and in untreated rats. MLL tumo r growth in rats treated with Ac-PHSCN-NH2 beginning 1 day after MLL cell i njection was reduced by 99.9% during the first 16 days of treatment, althou gh subsequent tumor growth occurred. MLL tumor cryosections immunostained w ith anti-PECAM-1 shelved that Ac-PHSCN-NH2 inhibited neovascularization by 12-fold during this time. Whether initiated after MLL cell injection or onl y after MLL tumor removal, Ac-PHSCN-NH2 treatment reduced the numbers of ML L lung colonies and micrometastases by 40- to >100-fold, whereas Ac-HSPNC-N H2 was inactive. Thus, Ac-PHSCN-NH2 may be a potent antitumorigenic and ant imetastatic agent for postsurgical use prior to extensive metastasis.