HeLa cell transformants overproducing mouse metallothionein show in vivo resistance to cis-platinum in nude mice.
Plasmid pSV2MT-I encoding mouse metallothionein-I (MT-I) designed to be expressed under the control of an SV40 promoter was introduced into human HeLa S3 cells. Several transformants (HeLa/MTH) carrying multi-copies of mouse MT-I cDNA in their genomes were isolated. These transformants produced 4 to 20-fold larger amounts of MT than their parent cells. The MT levels in HeLa/MTH were well correlated with the extent of resistance to cadmium, but not with that to cis-platinum (cis-DDP) in vitro. To study the role of MT in resistance to cis-DDP in vivo, nude mice were inoculated subcutaneously with two independent HeLa/MTH clones. MT levels in these tumors were about 3-fold higher than those in the parental cells. The growth of tumors derived from either HeLa/MTH clone was not inhibited in the presence of 15 micromol/kg of cis-DDP, which completely inhibited the growth of tumors derived from the parental HeLa cells. These data strongly suggest that the elevated level of MT confers resistance to cis-DDP in vivo but not in vitro. Thus, the results of this study indicate that in vitro determinations of the influence of MT on cis-DDP resistance may underestimate its importance in in vivo situations.
Toyoda
H
H
Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo.
Mizushima
T
T
Satoh
M
M
Iizuka
N
N
Nomoto
A
A
Chiba
H
H
Mita
M
M
Naganuma
A
A
Himeno
S
S
Imura
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D015152:Blotting, Northern; D015139:Blotting, Southern; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008668:Metallothionein / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D010957:Plasmids; D013997:Time Factors; D014162:Transfection
D000970:Antineoplastic Agents; D000975:Antioxidants; D008668:Metallothionein; D005978:Glutathione; D002945:Cisplatin