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Inhibition of Human Granulocyte Function by Methotrexate¹

Infectious Disease Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510 [J. S. H., J. A. M., R. K. R.], and Department of Pediatrics, Division of Oncology, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [M. H. D.]

Patients receiving cytotoxic drugs are at an increased risk of bacterial infection. Drug-induced leukopenia may be responsible for depression of host defenses; however, there is little information concerning the qualitative effects, if any, of cytotoxic agents on granulocyte antibacterial activity. Since methotrexate is now being used in massive doses in vivo, we investigated the effects of this drug on antibacterial and metabolic functions of normal polymorphonuclear leukocytes in vitro.

Phagocytosis, quantitative protein iodination, and staphylococcal killing of normal polymorphonuclear leukocytes were found to decrease with exposure to increasing concentrations of methotrexate. The effects of methotrexate on these cell functions were rapid in onset and readily reversed by washing the cells, suggesting a locus of action on the cell membrane rather than at the level of nucleic acid synthesis. Exposure of cells to similar concentrations of folic acid or folinic acid produced no impairment of bacterial phagocytosis, suggesting that the observed effects are specific for methotrexate. The concentrations of methotrexate that produced these impairments are readily achieved in vivo and may alter antibacterial defenses in patients receiving this therapy.

¹ This work was supported by USPHS Grants R01 AI 10600, 2 R10 CA 11796, 5 T12 CA 08147, 1 PO 2 CA 14489, and R01 AI 13251; a considerable portion of the work was performed in the Department of Medicine, University of Pennsylvania.

² Present address: Children's Hospital Medical Center, 200 Longwood Avenue, Boston, Mass. 02115.

³ Recipient of Research Career Development Award 5 K4 AI 70052 while at the University of Pennsylvania. To whom requests for reprints should be addressed, at Infectious Disease Section - 208 LCI, Yale University School of Medicine, 333 Cedar Street, New Haven, Conn. 06510.

Received 6/13/77. Accepted 12/ 2/77.