Cytostatic activity of cisplatin in the presence of WR2721 and its thiol metabolite WR1065 in OVCAR-3 human ovarian cancer cells as compared to V79 fibroblasts.
The effect of the modulating agent WR2721 (S-2-(3-aminopropylamino)ethylphosphorothioic acid, ethiofos) and its active thiol metabolite WR1065 on the cytostatic effect of cisplatin was investigated in a human ovarian cancer cell line OVCAR-3 and compared to that in V79 fibroblasts. WR1065 protected both OVCAR-3 and V79 cells against the cytostatic effect of cisplatin when incubated together with (co-incubation) or 15 min prior to (pre-incubation) the platinum drug. A dose-related effect up to complete protection was obtained when cells were coincubated with WR1065. Pre-incubation with WR1065 protected less and protection declined as cisplatin exposure time increased. A 60 min incubation of the cells with WR1065, starting 1 hr after a 60 min cisplatin exposure, did not protect OVCAR-3 and V79 cells from the cytostatic effect of cisplatin. The parent drug WR2721, up to a concentration of 0.01 M, did not protect OVCAR-3 and V79 cells when co-incubated with cisplatin. These results support the conclusions: a) that WR1065, and not the parent drug WR2721, is the protective species entering the cells, b) that prevention of damage is the main mechanism of protection and c) that tissues are expected to be protected by WR2721 only if WR1065 is formed and taken up by these tissues. Therefore, the preferential formation and uptake of WR1065 by non-tumour tissues is essential for a successful combination of WR2721 with platinum chemotherapy.
Treskes
M
M
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Nijtmans
L
L
Fichtinger-Schepman
A M
AM
van der Vijgh
W J
WJ
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D008624:Mercaptoethylamines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D008624:Mercaptoethylamines; D011838:Radiation-Sensitizing Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine; D002945:Cisplatin