Decreased sensitivity of carcinoembryonic antigen cDNA-transfected cells to adriamycin.
Carcinoembryonic antigen (CEA) is a heavily glycosylated protein and is expressed at a high frequency in adenocarcinomas, which are known to be one of the cancers most resistant to chemotherapeutic agents. In this study, with the aim to elucidate whether CEA participates in drug resistance or not, we tested the adriamycin (ADR) sensitivity of CEA transfectants of H-ras-transformed NIH 3T3 cells in vitro and in vivo. The ADR sensitivity of CEA transfectants in vitro was evaluated as growth (% of control) when incubated with various concentrations of ADR, and showed that they were higher than those of mock transfectants. The decreased ADR sensitivity of CEA transfectants in vivo was also observed as an increase in tumor size after intraperitoneal administration of ADR into SCID mice. To define the mechanisms for resistance, the accumulation and efflux of ADR in transfectants was examined. The rate of ADR accumulation in CEA transfectants was reduced compared to mock transfectants, caused at least partly by an increased efflux out of the cells. Furthermore, the modification of N-glycan on CEA by deoxymannojirimycin, an N-glycosylation processing inhibitor, partially restored ADR sensitivity of CEA transfectants, suggesting an involvement of sugar chains. Our data suggest that CEA expression may decrease ADR sensitivity of cancer cells.
Kawaharata
H
H
First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Japan.
Hinoda
Y
Y
Itoh
F
F
Endo
T
T
Oikawa
S
S
Nakazato
H
H
Imai
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000235:genetics*; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology*; D004352:Drug Resistance, Microbial / Q000235:genetics*; D005347:Fibroblasts; D051379:Mice; D014162:Transfection
D000903:Antibiotics, Antineoplastic; D002272:Carcinoembryonic Antigen; D018076:DNA, Complementary; D004317:Doxorubicin