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The development of VIP-ellipticine conjugates
Terry W Moody1, Gregory Czerwinski, Nadia I Tarasova
1Department of Health and Human Services, NCI Office of the Director, CCR, Building 31, Room 3A34, 31 Center Drive, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
Abstract:
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 (125)I-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 microM, 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 microM. Radiolabeled VIP-LALA-E was internalized at 37 degrees C 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-H1299 cells, cell viability decreased based on trypan blue exclusion and reduced 3H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC1 receptor-mediated endocytosis.
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