Melphalan and other anticancer modalities up-regulate B7-1 gene expression in tumor cells.
In this study, we show that administration of low-dose melphalan (l -PAM, l -phenylalanine mustard) to mice bearing a large MOPC-315 plasmacytoma led to a rapid up-regulation of B7-1 (CD80), but not B7-2 (CD86), expression on the surface of MOPC-315 tumor cells. This l -PAM-induced preferential up-regulation of B7-1 surface expression was due, at least in part, to a direct effect of l -PAM on the tumor cells, as in vitro exposure of MOPC-315 tumor cells to l -PAM led to the preferential up-regulation of B7-1 surface expression. Moreover, in vitro exposure of MOPC-315 tumor cells to two other anticancer modalities, gamma-irradiation and mitomycin C, resulted in the preferential up-regulation of B7-1 surface expression. This effect was not restricted to MOPC-315 tumor cells, as preferential up-regulation of B7-1 surface expression was observed also following in vitro exposure of the P815 mastocytoma (that is negative for both B7-1 and B7-2 surface expression) to any of the three anticancer modalities. The up-regulation of B7-1 surface expression following in vitro exposure of tumor cells to l -PAM, gamma-irradiation, or mitomycin C required de novo protein and RNA synthesis, and was associated with the accumulation of mRNA for B7-1 within 4-8 h, indicating that the regulation of B7-1 expression is at the RNA transcriptional level. These results have important implications for an additional immune-potentiating mechanism of these anticancer modalities in clinical setting.
Sojka
D K
DK
Department of Biochemistry and Molecular Biology, University of Illinois, Chicago 60612, USA.
Donepudi
M
M
Bluestone
J A
JA
Mokyr
M B
MB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000528:radiation effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D051940:B7-2 Antigen; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D004334:Drug Administration Schedule; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000276:immunology; D007274:Injections, Intraperitoneal; D012515:Mast-Cell Sarcoma; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D018906:Antineoplastic Agents, Alkylating; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D011506:Proteins; D016685:Mitomycin; D012313:RNA; D008558:Melphalan