Paradoxical effect of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on enhancing antitumor activity of cisplatin in ascites sarcoma 180 cells.
We investigated the enhancing effect of two metal-chelating compounds, 2,3-dimercapto-1-propanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA), on the antitumor activity of cisplatin (CDDP). In the in vivo experiments, DMPS showed a clear synergistic effect and significantly enhanced the antitumor activity of CDDP in terms of survival and life span in mice transplanted with ascites sarcoma 180 cells (S180 cells) at a dose of <100 micromol/kg, s.c., but not at a dose of >500 micromol/kg. On the other hand, DMSA did not enhance the antitumor activity of CDDP. DMPS (50 micromol/kg, s.c.) combined with CDDP also potently suppressed [(3)H]thymidine uptake in S180 cells implanted in mice, whereas DMSA did not. In the in vitro experiments, DMPS (10(-6) to 10(-5) M) produced a time- and dose-dependent decrease in intracellular Ca(2+) concentrations ([Ca(2+)](i)) in S180 cells and, in combination with CDDP, yielded a significant increase in intracellular platinum accumulation compared to that in cells treated with CDDP alone. These results indicate that DMPS used in combination with CDDP may be of considerable benefit in enhancing the cytotoxicity of CDDP in tumor cells, especially at a low dose. The results also suggest that the enhancing effect of DMPS is closely related to a decrease in [Ca(2+)](i) and that the suitable dose and adequate administrational time of DMPS are important for its effective action.
Sato
Toshihiro
T
Department of Pharmacology, Tokyo Dental College, Chiba, Japan.
Okubo
Migiwa
M
Sawaki
Kohei
K
Maehashi
Hiroshi
H
Kawaguchi
Mitsuru
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001201:Ascites / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000378:metabolism; D004113:Succimer / Q000008:administration & dosage*
D000970:Antineoplastic Agents; D004113:Succimer; D002945:Cisplatin