Fibrosarcoma Cell Line HT1080 Carrier-mediated Transport of Oligopeptides in the Human

To explore the feasibilityof targeting human tumor cells via their trans port systems, dipeptide uptake was Studied in the human fibrosarcoma cell line HT1OSOand the human fibroblast cell line IMR-90 by the use of hydrol ysis-resistant glycytsarcosine (Gly-Sar). The uptake of [†̃4CJGly-Sar into HT1OSOwas time dependent Kinetic analysis of the concentration depend ence ofthe initial rate of['4C)Gly-Sar uptake showed that a carrier-mediated transport system with a [email protected] ±33 [email protected] ±4.0 (nmolIl5 mhx/ing protein) and a nonsaturable component (kd of 0.80 @df15 mm/mg protein) were @p@nsibk for the dipeptide uptake by HT1OSOcells. The optimal pH for the maximal uptake was around 6.0. [†̃4C]Gly-Sar uptake was inhibited by various diand tripeptides and peptide-mimetic dnigs, such as bestatin and cefadroxil. [†̃4CJGIy-Sar uptake was not affected by the pr@ence of amino acids or tetraor pentapeptides. The uptake of cefadroxil was reduced significantly by unlabeled Gly-Sar. Moreover, Gly-Gly and GIy-Leu produced an increase in the apparent Km0f the uptake of Gly-Sar without altering V@. On the other hand, dipeptide uptake by IMR-90, which is a normal diploid cell line (not malignant), showed no saturable transport These results suggest that HT1OSOcells take up dipepddes via a pH-depend ent transporter. This is the first report showing that a dipeptide transport system, which is similar but not identical to the well-characterized oligopep tide transporters PepTi and PepT2, exists in fibroblast-denved tumor cells but not in normal fibroblasts. The present finding could be the basis ofa novel strategy for the specific delivery of oligopeptide-mimetic anticancer drugs