The development of VIP-ellipticine conjugates

The mechanism by which vasoactive intestinal peptide (VIP)-ellipticine (E) conjugates are cytotoxic for human lung cancer cells was investigated. VIP-alanyl-leucyl-alanyl-leucyl-alanine (ALALA)-E and VIP-leucyl-alanyl-leucyl-alanine (LALA)-E inhibited I-125-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 muM, respectively. VIP-ALALA-E and VIP-LALA-E caused elevation of cAMP in NCI-H1299 cells with ED50 values of 0.7 and 0.1 muM. Radiolabeled VIP-LALA-E was internalized at 37degreesC and delivered the cytotoxic E into NCI-H1299 cells. VIP-LALA-E inhibited the growth of NCI-H1299 cells in vitro. Three days after the addition of VIP LALA-E to NCI-HI299 cells, cell viability decreased based on trypan blue exclusion and reduced 3 H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC(1) receptor-mediated endocytosis. (C) 2004 Elsevier B.V. All rights reserved.