Drug resistance results in alterations in expression of immune recognition molecules and failure to express Fas (CD95).
It is demonstrated that methotrexate/cisplatin-sensitive L1210 cells express low levels of major histocompatibility complex (MHC) class II relative to the high levels expressed on methotrexate (MTX)/cisplatin-resistant L1210/DDP cells. L1210 cells express cell-surface Fas, while the L1210/DDP cells express no cell-surface Fas. Expression of costimulatory molecules B7-1/B7-2 and Fas is increased on L1210 cells, but not L1210/DDP, in the presence of methotrexate or trimetrexate (TMTX). Therefore, a component of the mechanism of action of some anti-cancer agents may be to facilitate immune recognition and T cell-directed, Fas-induced cell death. Loss of cell-surface Fas expression and failure of Fas (CD95)-dependent apoptotic death has been observed when cells develop drug resistance. The defect in apoptosis can be overcome by anti-cancer agents or experimental manipulation that induce Fas expression on the drug-resistant cells.
Department of Pharmacology, Vermont Cancer Center, University of Vermont College of Medicine, Burlington 05405, USA.
A
A
Bhushan
J L
JL
Kupperman
J E
JE
Stone
P J
PJ
Kimberly
N S
NS
Calman
M P
MP
Hacker
R B
RB
Birge
T R
TR
Tritton
M K
MK
Newell
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D018122:B7-1 Antigen / Q000096:biosynthesis*; D051940:B7-2 Antigen; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D007107:Immune System / Q000187:drug effects*; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D019311:Staurosporine / Q000494:pharmacology; D016597:Trimetrexate / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis*
D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D002273:Carcinogens; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D019311:Staurosporine; D016597:Trimetrexate; D008727:Methotrexate