Modulation of membrane transport of alkylating agents and amino acids by an analog of vasopressin in murine L5178Y lymphoblasts in vitro.
The synthetic vasopressin analog 1-deamino-8-D-arginine vasopressin (dDAVP) has been shown to influence a wide range of cell-membrane-related events. Accordingly, the effect of dDAVP on membrane transport of various alkylating agents and amino acids was evaluated in L5178Y lymphoblasts in vitro. dDAVP stimulated melphalan uptake but conversely inhibited uptake of nitrogen mustard, choline (the natural transport substrate for the nitrogen mustard carrier), and leucine. No effect on the uptake of cyclophosphamide or glutamine was observed. Increased melphalan uptake was due to effects on both substrate influx and efflux. The effect of dDAVP on melphalan influx was particularly complex: dDAVP stimulated melphalan influx by amino acid transport system ASC but inhibited influx by system L, resulting in a net increase in unidirectional drug influx. Melphalan efflux was inhibited by dDAVP. Decreased uptake of nitrogen mustard, choline and leucine was due, at least in part, to decreased substrate influx. However, the mechanisms of inhibition were dissimilar: inhibition of substrate influx was non-competitive for choline but competitive for leucine. In conclusion, dDAVP induced diverse but apparently specific effects on membrane transport of several alkylating agents and amino acids. Since the accumulation of alkylating agents such as melphalan within tumor cells is a major determinant of cytotoxicity, dDAVP may have a role as a biological response modifier.
D000477:Alkylating Agents / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005973:Glutamine / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D007930:Leucine / Q000378:metabolism; D007940:Leukemia L5178 / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D051379:Mice
D000477:Alkylating Agents; D000596:Amino Acids; D005973:Glutamine; D003520:Cyclophosphamide; D003894:Deamino Arginine Vasopressin; D007930:Leucine; D008558:Melphalan