Inhibition of hematopoietic tumor growth by combined treatment with deferoxamine and an IgG monoclonal antibody against the transferrin receptor: evidence for a threshold model of iron deprivation toxicity.
Recent studies have suggested that iron deprivation may represent a useful new approach in cancer therapy, and several strategies for producing such deprivation are now under investigation. Thus, for example, we recently provided evidence that combined treatment with the iron chelator deferoxamine and an IgG monoclonal antibody against the transferrin receptor (ATRA) produces synergistic inhibition of hematopoietic tumor cell growth in vitro (J. D. Kemp, K. M. Smith, L. J. Kanner, F. Gomez, J. A. Thorson, and P. W. Naumann, Blood, 76: 991-995, 1990). The current study is an attempt to analyze the mechanisms responsible for the synergistic interaction. The data show that a single IgG ATRA can produce up to 75% inhibition of iron uptake while having little effect on DNA synthesis; this suggests that tumor cells either take up or have stored amounts of iron well in excess of that required to support immediate metabolic needs. When deferoxamine and the IgG ATRA are used together, the effects on iron acquisition and receptor down-modulation are either additive or subadditive but are clearly not synergistic. Overall, the findings suggest that the IgG ATRA produces an injury to iron uptake that is just below a critical threshold and that the additional effect provided by the iron chelator is sufficient to exceed that threshold and produce a rapid depletion of iron pools that are vital for short-term DNA synthesis. IgG ATRAS thus seem to be of even greater interest as therapeutic reagents, and further study of their properties and of how they interact with deferoxamine appears to be warranted.
Kemp
J D
JD
Department of Pathology, University of Iowa College of Medicine, Iowa City 52242.
Thorson
J A
JA
Stewart
B C
BC
Naumann
P W
PW
D000818:Animals; D000911:Antibodies, Monoclonal; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007074:Immunoglobulin G; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D007700:Kinetics; D016399:Lymphoma, T-Cell; D051379:Mice; D008954:Models, Biological; D011990:Receptors, Transferrin / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D011990:Receptors, Transferrin; D007501:Iron; D003676:Deferoxamine