Cytotoxicity and DNA cross-linking activity of 4-sulfidocyclophosphamides in mouse leukemia cells in vitro.
Two sulfido derivatives of cyclophosphamide (CP), 4-S-(hexane-6-ol)-sulfidocyclophosphamide and 4-S-(propionic acid)-sulfidocyclophosphamide, were studied for their in vitro cytotoxicity against L1210 cells and for their DNA-damaging effects in these cells. These derivatives spontaneously hydrolyze under physiological conditions to form 4-hydroxycyclophosphamide, the active metabolite of cyclophosphamide. The two derivatives were compared with phosphoramide mustard, the presumed alkylating species generated by 4-hydroxycyclophosphamide decomposition, for cytotoxic and DNA cross-linking actions. The three compounds yielded colony survival curves that were similar in shape, but the sulfido derivatives were 4 or 5 times as potent as was phosphoramide mustard. All three compounds produced DNA-protein cross-links as well as interstrand cross-links as measured by alkaline elution. The time course of cross-link formation and removal for the three compounds was similar. The sulfido compounds, however, were 4 to 5 times as potent as was the phosphoramide mustard in the formation of interstrand cross-links, in agreement with the cytotoxicity findings. The higher potency of the sulfido compounds was not attributable to the generation of acrolein. These findings indicate that sulfido derivatives of CP can act directly (without metabolic activation) on cells, probably through spontaneous stepwise conversion to phosphoramide mustard, the presumed proximal alkylating agent. The cell-killing effect may be mediated by phosphoramide mustard-induced DNA interstrand cross-linking. Sulfidocyclophosphamide CP derivatives appear to be suitable for in vitro studies of the mechanism of action of CP. Sulfidocyclophosphamide CP derivatives may also have therapeutic potential as CP-like drugs that do not require metabolic activation.
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000633:toxicity*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000633:toxicity; D004273:DNA, Neoplasm / Q000378:metabolism*; D006868:Hydrolysis; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010752:Phosphoramide Mustards / Q000378:metabolism; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010752:Phosphoramide Mustards; C028135:4-S-(hexane-6-ol)sulfidocyclophosphamide; C028136:4-S-(propionic acid)sulfidocyclophosphamide; D003520:Cyclophosphamide