Reduction in the toxicity of aminopterin--monoclonal-antibody conjugates by leucovorin.
Although aminopterin(AMN)-antibody drug conjugates have been demonstrated to have a greatly increased antitumor efficacy compared to the free drug, their use is limited by an increase in systemic toxicity manifested by weight loss and bone marrow suppression. Using a murine thymoma model (E3) in inbred mice, the toxicity of a sublethal dose of free AMN could be prevented by the administration of leucovorin 24 h following drug treatment, whilst maintaining the antitumour effect of the drug. The same rescue protocol completely abrogated the antitumour efficacy of AMN-antibody, although toxicity was also diminished. However, the later administration of leucovorin 48-72 h following a sublethal dose of AMN-antibody conjugates resulted in a maintenance of the anti-tumour efficacy of the immunoconjugates and a reduction in toxicity, with a mean percentage change in mouse weight not significantly different from that of the controls. These studies demonstrate that reversal of toxicity caused by AMN-antibody conjugates can be achieved by leucovorin while maintaining a powerful antitumour effect provided that the dose of leucovorin is administered 48-72 h after the conjugate.
Rowland
A J
AJ
Austin Research Institute, Austin Hospital, Heidelberg, Vic, Australia.
Pietersz
G A
GA
D000630:Aminopterin / Q000633:toxicity*; D000818:Animals; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly / Q000276:immunology; D000922:Immunotoxins / Q000032:analysis / Q000627:therapeutic use*; D002955:Leucovorin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013945:Thymoma / Q000188:drug therapy; D013953:Thymus Neoplasms / Q000188:drug therapy
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D000922:Immunotoxins; D000630:Aminopterin; D002955:Leucovorin