Chlorambucil inhibition by dimethyl sulfoxide and thiosulfate: implications for chlorambucil chemotherapy.
Chlorambucil alkylation of pyridine, a model for nucleotides, appears to be first order in chlorambucil, but zero order in pyridine, and is strongly inhibited by dimethylsulfoxide. The same results are seen with chlorambucilyl [3H]prolyl proline; full alkylation activity was regained upon removal of dimethylsulfoxide. Chlorambycilyl [3H]prolyl proline alkylation of tRNA also appears to be first order in alkylator, but somewhat dependent on tRNA concentration, and is also strongly inhibited by dimethylsulfoxide. 10 mM Na2S2O3 completely inhibits alkylation by aqueous 1 mM chlorambucil. Up to 1 M chlorambucil in Me2SO retains full alkylation activity for at least a year. We suggest that the risk of carcinogenesis inherent in chlorambucil chemotherapy may be avoided by the topical application or injection of 1 M chlorambucil in Me2SO, in conjunction with oral administration of Na2S2O3.
D000478:Alkylation; D000818:Animals; D002699:Chlorambucil / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D004121:Dimethyl Sulfoxide; D007700:Kinetics; D011392:Proline; D012343:RNA, Transfer; D013885:Thiosulfates
D013885:Thiosulfates; D002699:Chlorambucil; D012343:RNA, Transfer; D011392:Proline; D004121:Dimethyl Sulfoxide