title: Evidence for increased intracellular transport of m-sarcolysine (alkylating moiety) when combined with two amino acid analogs (PTT-119).
abstract: PTT-119 is an antineoplastic agent in which an alkylating moiety, m-sarcolysine, is linked to two amino acid analogs. Previous studies showed a higher "in vitro" cytotoxicity of PTT-119 when compared to free m-sarcolysine; the mechanisms of this enhanced activity are not completely understood. In this study we incubated peripheral blood cells from 8 chronic lymphocytic leukemia patients with both m-sarcolysine and equimolar concentrations of PTT-119, measuring the intracellular concentration of the alkylating moiety. We observed a significantly higher intracellular concentration of m-sarcolysine in cells incubated with the peptide-bound drug than with the free drug (58.3 +/- 39.6 versus 4.4 +/- 1.9 ng/10(6) cells; P = 0.013). This observation could explain the higher cytotoxic activity of PTT-119 and the lack of cross-resistance with melphalan.
authors: L. e A. Seràgnoli Haematology Institute, University of Bologna, Italy.
authors: F
authors: F
authors: Verlicchi
authors: S
authors: S
authors: Boschi
authors: G
authors: G
authors: Visani
authors: A
authors: A
authors: Guidi
authors: P
authors: P
authors: Tosi
authors: M
authors: M
authors: Cavo
authors: S
authors: S
authors: Tura
mesh_terms: D000596:Amino Acids / Q000493:pharmacokinetics*; D001692:Biological Transport; D004338:Drug Combinations; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008558:Melphalan / Q000493:pharmacokinetics*; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics*; D009994:Osmolar Concentration
chemical_list: D000596:Amino Acids; D004338:Drug Combinations; D009588:Nitrogen Mustard Compounds; C038259:ambamustine; D008558:Melphalan