Int. d. Irnmunopharmac., Vol. 17, No 1, pp. 1-7, 1995 Elsevier Science Ltd Pergamon Copyright © 1995 International Society for lmmunopharmacology Printed in Great Britain. All rights reserved 0192-0561/95 $9.50 + .00 0192-0561 (94)00083-2 EFFECT OF CISPLATIN AND FK565 ON THE ACTIVATION OF TUMOR- ASSOCIATED AND BONE MARROW-DERIVED MACROPHAGES BY DALTON'S LYMPHOMA PRAHLAD PARAJULI, SUKH MAHENDRA SINGH* and ASHOK KUMAR Cellular Immunology Laboratory, Department of Zoology, University of Delhi, Delhi-110 007, India (Received 13 April 1994 and in final form 17 September 1994) Abstract - - The present investigations were undertaken to study the effect of Dalton's lymphoma (DL) in situ on the functions of DL-associated macrophages (DL-AM)and bone marrow-derivedmacrophages (BMDM) in C3H/He mice. DL-AM showed enhanced production of reactive nitrogen intermediates (RNI) and tumor necrosis factor (TNF) compared with normal peritoneal macrophages (NMO). BMDMof DL mice also showed enhanced production of RNI compared with BMDM of normal mice. These observations suggest that the presence of DL in situ creates an environment which favours the activation of both DL-AM and macrophage progenitors located at a distant site. The effect of in vivo administration of chemotherapeutic drugs cisplatin and FK565 on the activation of DL-AM by DL cells was also investigated. Both cisplatin and FK565 augmented RNI production of NMO but differed in their effect on DL-AM. The production of RNI by DL-AM of cisplatin-treated mice was inhibited, whereas in the FK565 group it was up-regulated. Keywords: tumor-associated macrophages, bone marrow-derived macrophages, Dalton's lymphoma, reactive nitrogen intermediates, tumor necrosis factor. Macrophages represent a major component of the lymphoreticular infiltrate of tumors (Evans & Haskill, 1983; Mantovani et al., 1986). Considerable progress has been made in the definition of the origin, regulation and function of macrophages that infiltrate tumors. However, several aspects of the immunobiology of tumor-associated macrophages (TAM) remain obscure. TAM have pleiotropic functions that can influence tumor growth and progression in opposite directions. The outcome depends on the sum of individual func- tions, dictated by the activation state of macrophages and the intrinsic properties of tumor cells (Mantovani et al., 1986, 1992). It remains to be established whether TAM can be therapeutically modulated to express anti- tumor activity. TAM from growing tumors have cytolytic potential that can be enhanced by in vitro stimulation (McBride, 1986; Brunda et al., 1991; Mantovani et al., 1993). In vitro co-incubation of macrophages with tumor cells or their products has been shown to both up- and down-regulate macrophage activation (Szuro-sudol et al., 1983; Hasday et al., 1990; Janicke & Mannel, *Author to whom correspondence should be addressed. 1990; Sotomayor et al., 1991; Mantovani et al., 1992; Hannigan et al., 1992; Zembala et al., 1994). Our studies on the in vitro interactions of murine peritoneal macrophages and Dalton's lymphoma (DL), a spontaneous T-cell lymphoma, have demon- strated that DL cells inhibit the tumoricidal activity of macrophages (Singh et al., 1992). In the above study macrophages were obtained from normal mice and then co-incubated with DL cells in vitro. However, the effect of DL cells on the functions of DL-associated peritoneal macrophages (DL-AM) is not understood. In view of these observations the present investiga- tions were undertaken to study: (a) the effect DL cells on the function of DL-associated macrophages (DL-AM) in situ; (b) the effect of in vivo administration of chemotherapeutic drug cisplatin and a synthetic biological response modifier (BRM), FK565 on the functions of DL-AM; and (c) whether DL induced modulation of macrophage is a local phenomenon or DL cells elaborate soluble mediators that can affect the functions of macrophages located even at distant sites.