Cytotoxicity and DNA cross-linking induced by peptide conjugated m-L-sarcolysin in human melanoma cells.
Peptichemio is a complex of six peptides containing m-L-sarcolysin which is used in cancer chemotherapy. One of the peptides, L-propyl-m-sarcolysyl-L-p-fluorophenylalanine (PSF), is highly toxic to melanoma cells. We have compared the effects of melphalan, m-L-sarcolysin and PSF on human melanoma cell lines. PSF was 35-fold and 28-fold more toxic to RPMI 8322 melanoma cells than melphalan and m-L-sarcolysin, respectively. Similar differences in the cytotoxic effects of PSF and m-L-sarcolysin were also seen with two other melanoma cell lines. The cytotoxicity of both PSF and m-L-sarcolysin to RPMI 8322 melanoma cells was potentiated by depletion of cellular glutathione. Both PSF and m-L-sarcolysin caused a protracted induction of DNA cross-links in RPMI 8322 cells, with maximum at 24 hours after drug exposure. PSF induced 9-fold higher levels of DNA interstrand cross-links than m-L-sarcolysin, indicating that the increased cytotoxicity of this drug is associated with a more efficient induction of DNA damage.
Hansson
J
J
Department of General Oncology, Karolinska Hospital, Stockholm, Sweden.
Lewensohn
R
R
Ringborg
U
U
D004273:DNA, Neoplasm / Q000187:drug effects*; D004151:Dipeptides / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000737:chemistry / Q000235:genetics*; D008558:Melphalan / Q000031:analogs & derivatives* / Q000633:toxicity*; D009842:Oligopeptides; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010135:p-Fluorophenylalanine / Q000031:analogs & derivatives* / Q000633:toxicity
D004273:DNA, Neoplasm; D004151:Dipeptides; D009842:Oligopeptides; C072240:propyl-3-sarcolysin-4-fluorophenylalanine; C053596:metamelfalan; D010135:p-Fluorophenylalanine; D005978:Glutathione; D008558:Melphalan