Cisplatin combined with tiopronin or sodium thiosulfate: cytotoxicity in vitro and antitumor activity in vivo.
We have previously reported that the thiol compound tiopronin protects rat kidneys in vitro against the toxic activity of cisplatin. The influence of tiopronin and sodium thiosulfate (STS) on the cytotoxicity of cisplatin has been investigated on P388 leukemic cells in vitro after 3 days. The combination has also been investigated in vivo in BDF1 mice bearing a P388 s.c. tumor. In contrast to STS, tiopronin did not significantly reduce the cytotoxic activity of cisplatin in vitro and nor did it affect the uptake of platinum (cisplatin-derived), binding to DNA or the percentage of interstrand cross-links (%ISCL) formation. The co-administration of cisplatin (4 mg/kg) and tiopronin (150 and 300 mg/kg) to BDF1 female mice bearing a s.c. P388 tumor produced a significant reduction in tumor growth similar to that of a single 6 mg/kg dose of cisplatin. Interestingly, pre-incubation in vitro of either tiopronin or STS for 2 h with the species formed from cisplatin by hydrolysis demonstrated their ability in inhibiting the cytotoxicity of these reactive platinum products. These results indicate that tiopronin does not reduce the cytotoxicity of cisplatin in vitro, as STS does. This may be, at least partly, because of a different effect of the two thiol compounds on the cellular uptake and binding of platinum to DNA. Notably, tiopronin substantially reduced tumor growth in mice treated with a non-toxic dose of cisplatin (p < or = 0.0277), suggesting some positive influence of this thiol compound on the antitumor properties of cisplatin. The ability of tiopronin to protect in vitro against the cytotoxicity of the aquation products of cisplatin may be related to its nephroprotective effect.
Viale
M
M
Istituto Nazionale per la Ricerca sul Cancro, Servizio di Farmacologia Tossicologica, Genova, Italy. viale@hp380.ist.unige.it
Zhang
J G
JG
Pastrone
I
I
Mariggiò
M A
MA
Esposito
M
M
Lindup
W E
WE
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002945:Cisplatin / Q000627:therapeutic use* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D051381:Rats; D013885:Thiosulfates / Q000494:pharmacology* / Q000627:therapeutic use; D008625:Tiopronin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000931:Antidotes; D013885:Thiosulfates; D008625:Tiopronin; C017717:sodium thiosulfate; D002945:Cisplatin