Determinants of tamoxifen sensitivity control the nature of the synergistic interaction between tamoxifen and cisplatin.
The cytotoxic effect of tamoxifen (TAM) was investigated in the T-289 melanoma cell line, as well as the 289 DDP3 cisplatin (DDP)-resistant and the 289 TAM6 TAM-resistant variant melanoma cell lines to determine the effect of drug resistance on synergy. T-289 melanoma cells were made DDP or TAM resistant through chronic exposure to increasing concentrations of the respective drugs. Whereas DDP resistance could be overcome by increasing the concentration of TAM, the development of TAM resistance completely abolished synergy. TAM resistance was not related to the development of estrogen receptors, decreased TAM uptake, or the increased expression of the mdr-1 gene. TAM did not inhibit the action of Topoisomerase 1; however, TAM did induce apoptosis in the 289 melanoma cells. In contrast, TAM did not induce apoptosis in the TAM-resistant variant 289 TAM6 cells. To our knowledge, these are the first data associating TAM resistance with the inhibition of apoptosis.
McClay
E F
EF
Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston 29425, USA.
Jones
J A
JA
Winski
P J
PJ
Albright
K D
KD
Christen
R D
RD
Howell
S B
SB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D004264:DNA Topoisomerases, Type I; D002945:Cisplatin