This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Son, K. Articles by Kim, Y.-M. Search for Related Content PubMed PubMed Citation Articles by Son, K. Articles by Kim, Y.-M.

In Vivo Cisplatin-exposed Macrophages Increase Immunostimulant-induced Nitric Oxide Synthesis for Tumor Cell Killing¹

Department of Pharmaceutics, Rutgers, The State University of New Jersey, College of Pharmacy, Piscataway, New Jersey 08855 [K. S.], and Department of Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213 [Y-M. K.]

Mice pre-exposed to cisplatin increased their production of nitric oxide (NO) when treated with lipopolysaccharide (LPS). Peritoneal macrophages, isolated from mice 11 days after cisplatin treatment and cultured with LPS plus IFN-, increased NO production, whereas the macrophages isolated 2 days after cisplatin treatment decreased it. In both cases, NO was not produced without immunostimulant(s). Northern and Western Blot analysis showed that macrophages exposed to cisplatin for 11 days increased production of mRNA and protein expression of inducible nitric oxide synthase (iNOS). This result indicated that macrophages became more sensitive to LPS and IFN- when they were exposed to cisplatin in vivo. Peritoneal macrophages, when activated with LPS plus IFN- and then cocultured with several tumor cells, exhibited cytotoxic activity against both cisplatin-sensitive and cisplatin-resistant tumor cells. There was no difference in cytotoxicity between the paired cells. Under the same experimental condition, macrophages that were exposed to cisplatin for 11 days had significantly increased their cytotoxicity to the tumor cells. This cytotoxic activity was inhibited by the NOS inhibitor N^G-monomethyl-^l-arginine, indicating that NO is a major effector for macrophage-mediated tumor cell killing. Treatment of tumor cells with S-nitroso-N-acetylpenicillamine, a NO-generating compound, showed the similar tumoricidal effect. These data demonstrated that injection of cisplatin into the mice can enhance the sensitivity of macrophages to the subsequent treatment of immunostimulant(s) for effective tumor cell killing through enhanced NO production.

¹ Supported in part by the Charles and Johanna Busch Memorial Fund at Rutgers, The State University of New Jersey, Picataway, NJ.

² To whom requests for reprints should be addressed, at Department of Pharmaceutics, College of Pharmacy, Rutgers University, P. O. Box 789, Piscataway, NJ 08855.

Received 8/15/95. Accepted 10/18/95.

This article has been cited by other articles:

				A. R. Wewel, J. A. M. Crusius, U. Gatzemeier, M. Heckmayr, G. Becher, H. Magnussen, R. A. Jorres, and O. Holz Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy. Eur. Respir. J., May 1, 2006; 27(5): 1033 - 1039. [Abstract] [Full Text] [PDF]

				P. Ranjan, P. Shrivastava, S. M. Singh, A. Sodhi, and N. H. Heintz Baculovirus P35 inhibits NO-induced apoptosis in activated macrophages by inhibiting cytochrome c release J. Cell Sci., June 15, 2004; 117(14): 3031 - 3039. [Abstract] [Full Text] [PDF]

				K. Mortensen, J. Skouv, D. M. Hougaard, and L.-I. Larsson Endogenous Endothelial Cell Nitric-oxide Synthase Modulates Apoptosis in Cultured Breast Cancer Cells and Is Transcriptionally Regulated by p53 J. Biol. Chem., December 31, 1999; 274(53): 37679 - 37684. [Abstract] [Full Text] [PDF]

				Y.-M. Kim, R. V. Talanian, J. Li, and T. R. Billiar Nitric Oxide Prevents IL-1{beta} and IFN-{gamma}-Inducing Factor (IL-18) Release from Macrophages by Inhibiting Caspase-1 (IL-1{beta}-Converting Enzyme) J. Immunol., October 15, 1998; 161(8): 4122 - 4128. [Abstract] [Full Text] [PDF]

				Y.-M. Kim, M. E. de Vera, S. C. Watkins, and T. R. Billiar Nitric Oxide Protects Cultured Rat Hepatocytes from Tumor Necrosis Factor-alpha -induced Apoptosis by Inducing Heat Shock Protein 70Expression J. Biol. Chem., January 10, 1997; 272(2): 1402 - 1411. [Abstract] [Full Text] [PDF]