In vitro modulating effect of the reversible protein synthesis inhibitor zilascorb (2H) on cis-diamminedichloroplatinum (II)-induced cytotoxicity.
Zilascorb (2H) (5,6-benzylidene-d1-L-ascorbic acid sodium salt), a derivative of deuterated benzaldehyde inducing reversible protein synthesis inhibition, was tested on human NHIK 3025 cells in combination with the anticancer drug cis-diamminedichloroplatinum(II) (cis-DDP). The inactivating effect of cis-DDP, measured as loss of colony forming ability, was found to increase when a non-toxic treatment with zilascorb (2H) was given simultaneously with, or shortly prior to, treatment with cis-DDP. No potentiating effect was seen when zilascorb (2H) treatment occurred after removal of cis-DDP. Furthermore, the data showed that the potentiating effect of zilascorb (2H) reached a maximum at concentrations of between 2 and 4 mM. The underlying mechanism for this potentiation is unknown, but could possibly be related to the effect of zilascorb (2H) on protein synthesis. Alternatively, it is also possible that generation of free radicals from the ascorbate moiety of the zilascorb (2H) molecule may increase cellular damage induced by cis-DDP, or inhibit repair or restitution of cis-DDP-induced damage. Also, in cells of a cis-DDP-resistant subline, NHIK 3025/DDP zilascorb (2H) was found to potentiate the effect of cis-DDP. The cis-DDP-resistant cells, however, were found to be partly cross-resistant to cytotoxic treatments with zilascorb (2H).
Melvik
J E
JE
Institute for Cancer Research, Norwegian Radium Hospital, Montebello, Oslo.
Dornish
J M
JM
Larsen
R O
RO
Børretzen
B
B
Oftebro
R
R
Pettersen
E O
EO
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D011500:Protein Synthesis Inhibitors; D001205:Ascorbic Acid; D002945:Cisplatin; C070680:zilascorb