Enhancement of pulmonary metastases induced by decreased lung natural killer cell activity.

Administration of repeated high doses of 7.5 mg chlorozotocin [(CZT) CAS: 54749-90-5]/kg to syngeneic WAG rats bearing the rhabdomyosarcoma 9-4/0 enhanced the incidence of spontaneous metastasis compared to its incidence in untreated rats. This enhancement was observed concomitantly with an increase in the survival of 9-4/0 rhabdomyosarcoma and P 77 fibrohistiocytoma tumor cells, labeled with [125I]5-iodo-2'-deoxyuridine or 51Cr and injected iv. Within the first 24 hours after P 77 cell injection, the lungs retained 10% of the cells while the lungs of controls or of rats given one CZT injection only retained 0.06%. The natural killer (NK) cell cytotoxicity of cells flushed out from lung capillaries [lung intracapillary cells (LIC)] was studied concomitantly in a 4-hour 51Cr release assa against YAC-1 and P 77 target cells. A large reduction was again observed in NK cytotoxicity but only after repeated injections of 7.5 mg CZT/kg. Lung defenses were gradually restored after treatment stopped. Administration of polyinosinic-polycytidylic acid with CZT restored the NK cell cytotoxicity of LIC and inhibited lung metastases amplification. The close relationship between metastasis and NK activity indicates the need for caution as regards the effects of chemotherapy on NK activity.