Differences in the inhibition of translation by cisplatin, transplatin, and certain related compounds.
The non-therapeutic cisplatin congeners transplatin and chloroethylenetriamine platinum (dien) inhibited translation to a similar extent as cisplatin did. The IC50 values were: cisplatin 23 microM, transplatin 54 microM, and dien 117 microM. Unlike certain heavy metal inhibitors of translation, the effect of neither cisplatin nor the congeners was reversed by 3':5'-cyclic adenosine monophosphate (cAMP). This suggests that the effect of these platinum compounds does not occur by the heavy metal mechanism. Polyribosomes and ribosomal subunits formed in transplatin-inhibited reactions differed from those in reactions inhibited by cisplatin. Specifically, large polyribosomes and complete 80S ribosomal subunits accumulated in the presence of transplatin. This indicates that while cisplatin slowed initiation of peptide synthesis, the trans-isomer slowed elongation. Substantive differences were not found between cisplatin and the monofunctional compound dien. This congener increased the non-peptidyl disintegrations per minute in the acid precipitates of assays containing [35S]methionine. The high background indicated that an interaction between the label and a precipitable component of the system was induced by dien. However, consumption of methionine by this interaction did not appear to be the cause of the inhibition. Although there may be differences in the mechanisms of the effects, the finding that the non-therapeutic congeners inhibit translation at similar concentrations as cisplatin suggests that this inhibition is not responsible for the anticancer effect. On the other hand, the possibility that decreased translation could play an important role in the toxicity of these compounds in certain quiescent cells cannot be ruled out.
Sato
P H
PH
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Rosenberg
J M
JM
Sato
R I
RI
D000818:Animals; D002474:Cell-Free System; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000494:pharmacology; D008627:Mercuric Chloride / Q000494:pharmacology; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D012156:Reticulocytes; D013329:Structure-Activity Relationship
D011500:Protein Synthesis Inhibitors; C032799:chlorodiethylenetriamine platinum; C034697:transplatin; D008627:Mercuric Chloride; D000242:Cyclic AMP; D002945:Cisplatin