Enhancement of sensitivity to platinum(II)-containing drugs by 12-O-tetradecanoyl-phorbol-13-acetate in a human ovarian carcinoma cell line.
Sensitivity to platinum-containing drugs is believed to be a function of how much drug enters the cell, the extent of DNA adduct formation and the rate at which DNA is repaired. Activation of protein kinase C by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was found to enhance the sensitivity of human ovarian carcinoma 2008 cells to cisplatin (DDP), carboplatin (CBDCA) and (glycolato-O,O') diammineplatinum(II) (254-S). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C13*5.25 subline to each of the three drugs to the same extent as for the 2008 cells. TPA produced no significant change in the uptake of [3H]cis-dichloro(ethylenediamine)-platinum(II). ([3H]DEP) or CBDCA. It did not alter glutathione content or glutathione-S-transferase activity, and induced rather than suppressed metallothionein IIA mRNA levels. TPA did increase the formation of intrastrand guanine-guanine cross-links by a factor of 1.5 +/- 0.3 (s.d.), and reduced the fraction of intrastrand adducts removed from DNA over the subsequent 24 h by a factor of 1.3 +/- 0.2 (s.d.) (n = 4; P < 0.05), however, these effects were too small to account for the degree of TPA-induced sensitisation. These results indicate that the mechanism of TPA-induced sensitisation is not specific to any one structural form of platinum-containing drug, and that it is not readily explicable on the basis of an effect on the four major parameters currently believed to regulate DDP sensitivity.
Isonishi
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S
Department of Obstetrics and Gynecology, Jikei University, Tokyo, Japan.
Hom
D K
DK
Eastman
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A
Howell
S B
SB
D016190:Carboplatin / Q000378:metabolism* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000378:metabolism* / Q000493:pharmacokinetics; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology; D004273:DNA, Neoplasm / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D010051:Ovarian Neoplasms / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D011720:Pyrazoles / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; D011720:Pyrazoles; C002892:platinum ethylenediamine dichloride; C059597:monochlorobimane; C053989:nedaplatin; D016190:Carboplatin; D005982:Glutathione Transferase; D011493:Protein Kinase C; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin