Dichloromethylene diphosphonate (Cl2MDP) reduces natural killer (NK) cell activity in mice

Abstract

Daily administration of dichloromethylene diphosphonate (Cl₂MDP) to (C57BL/6 × DBA/2) F1 hybrid mice, from twc days of age (10 mg of P/kg body weight), resulted in a marked impairment of natural killer (NK) activity of spleer cells against YAC-1 lymphoma cells. The suppressive effecl increased with the duration of the treatment. Cessation of the treatment led to a rapid recovery (in 2 weeks) of NK activity while the osteopetrosic bone lesions persisted, Thus, the loss of natural killing cannot be explained by the simple reduction of bone marrow volume secondary to Cl₂MDP-induced osteopetrosis. However, as NK cells are considered to be dependent on the bone marrow because they cannot be sustained by extramedullary production, a direct effect of Cl₂MDP on the generation of NK cell precursors by the bone marrow was not excluded. Cl₂MDP was not directly toxic to the fully differentiated splenic NK cells, since the addition of Cl₂MDP to the in vitro assay (10⁻⁵ − 10 μg/ml) did not reduce cytotoxicity.

These studies suggest that impairment of NK activity during Cl₂MDP treatment may have clinical toxicologic implications since NK cells have been suggested to play an important role in natural host defenses against infection and neoplasia.