Modulation of cis-diamminedichloroplatinum (II) accumulation and cytotoxicity by spermine in sensitive and resistant human ovarian carcinoma cells.
The effect of spermine (Sp), a natural polycationic amine, on cisplatin (CDDP) sensitivity and accumulation of a human ovarian CDDP-sensitive cell line (2008) and its resistant variant (C13*) was investigated. Survival was also studied. The C13* cells were approximately 20-fold resistant to CDDP, yet were found to be just as sensitive to Sp as 2008 cells. When Sp was concurrently added with CDDP to the colony-forming assay, the IC50 dose was approximately 3-fold lower than that of CDDP alone. This decrease was the result of a synergistic interaction, as assessed by median effect analysis. The incubation of cells with the approximate IC50 dose of Sp for 1-8 h indicated that this synergism could be due to stimulation of CDDP accumulation, showing maximal uptake after 4 h of Sp exposure. This stimulation may be the result of a modulation of cellular membrane permeability by Sp, as assessed by the accumulation of [3H]mannitol. Exposure to Sp concentrations active on CDDP uptake also significantly increased [3H]mannitol accumulation in both cell lines. The triamine spermidine (Spd) did not significantly affect either the sensitivity of the two cell lines or CDDP and [3H]mannitol accumulation. These results suggest that Sp is a positive modulator of CDDP uptake, and thus of its cytotoxicity, even in resistant cells, where the phenotype is partly due to a CDDP accumulation defect.
Marverti
G
G
Department of Pharmacology, Georgetown University, Washington, District of Columbia 20007, USA.
Andrews
P A
PA
Piccinini
G
G
Ghiaroni
S
S
Barbieri
D
D
Moruzzi
M S
MS
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D002463:Cell Membrane Permeability; D002945:Cisplatin / Q000378:metabolism* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008353:Mannitol / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D011073:Polyamines; D013096:Spermine; D008353:Mannitol; D002945:Cisplatin