Accumulation modes of alkylating agents on normal peripheral blood lymphocytes

The in vitro uptake by normal peripheral blood lymphocytes of 14C-labeled cyclophosphamide and nitrogen mustard has been measured in a manner which parallels cell exposure to drugs used in the nitrogen mustard-oncovin-procabazine-prednisone (MOPP) and cyclophosphamide-oncovin-procarbazine-prednisone (COPP) clinical protocols. Accumulation of these alkylating agents occurs in two recognizable patterns. The first exhibits a saturation phenomenon, since radioactivity can be partially blocked by an equal concentration of unlabelled drug, reflects stereospecificity, and represents a minor fraction of total deposition. The second form, proportionately larger than the first, is dependent on drug concentration in the suspending medium, with radioactivity increasing in an apparently limitless linear fashion, uninfluenced by competitive inhibition. This part also is less tenaciously held by the lymphocyte. While the mere presence of drug on the lymphocytes does not necessarily imply injury or lethality, the fact that these peripheral lymphocytes are able to accumulate cytotoxic agents and are partially interchangeable with an analogous fixed lymphoid cell mass suggests that clinical immunosuppression and lymphocytopenia may be related, in part, to cell drug deposition.