The role of drug transport in resistance to nitrogen mustard and other alkylating agents in L518Y lymphoblsts.
An investigation was undertaken of the mechanism of resistance to nitrogen mustard (HN2) and other alkylating agents, with particular emphasis on the interaction between cross-resistance and drug transport mechanisms in L5178Y lymphoblasts. Dose-survival curves demonstrated that the D0 for HN2-sensitive cells (L5178Y) treated with HN2 in vitro was 9.79 ng/ml and the D0 for HN2-resistant cells (L5178Y/HN2) was 181.11 ng/ml; thus, sensitive cells were 18.5-fold more responsive than were resistant cells and the difference was highly significant (p less than 0.001). A similar evaluation of 5 additional alkylating agents, including chlorambucil, melphalan, 1,3-bis(2-chloroethyl)-l-nitrosourea, Mitomycin C, and 2,3,5-tris(ethyleneimino)-1,4-benzoquinone, revealed that L5178Y/HN2 cells were also cross-resistant, in part, to each of these compounds. Furthermore, the degree of cross-resistance was remarkably similar; for each drug, dose-survival studies showed that HN2-resistant cells were approximately 2- to 3-fold more resistant to therapy than were sensitive cells. L5178Y/HN2 cells were also cross-resistant to cyclophosphamide in vivo; after treatment with cyclophosphamide, DBA/2 female mice that were given inoculations of L5178Y cells, but not those given transplants of L5178Y/HN2 cells, showed a significant prolongation of survival time (p less than 0.01). Transport of HN2, hydrolyzed derivative of HN2 and choline by L5178Y lymphoblasts in vitro was not competitively inhibited by any of the other alkylating agents, suggesting that transport of these compounds was by an independent mechanism. These findings suggest that the mechanism whereby L5178Y/HN2 cells are cross-resistant to other alkylating agents may involve nontransport factors and that these other drugs may bypass a major portion of HN2 resistance by using independent transport systems.
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002330:Carmustine / Q000633:toxicity; D002460:Cell Line; D002699:Chlorambucil / Q000633:toxicity; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D007942:Leukemia, Experimental / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008466:Mechlorethamine / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D008558:Melphalan / Q000633:toxicity; D051379:Mice; D008811:Mice, Inbred DBA; D008937:Mitomycins / Q000633:toxicity
D000477:Alkylating Agents; D008937:Mitomycins; D002699:Chlorambucil; D008466:Mechlorethamine; D003520:Cyclophosphamide; D008558:Melphalan; D002330:Carmustine