Relationships between the in vitro cytotoxicity and transport characteristics of pirarubicin and doxorubicin in M5076 ovarian sarcoma cells, and comparison with those in Ehrlich ascites carcinoma cells.
OBJECTIVE
We sought to determine whether the de novo resistance of M5076 ovarian sarcoma cells, which show sensitivity to pirarubicin (THP), to doxorubicin (DOX) is due to differences in the transport characteristics between THP and DOX, and the results were compared with those for drug-sensitive Ehrlich ascites carcinoma cells.


METHODS
The in vitro cytotoxicity of the drugs was assessed by means of the tetrazolium dye assay. Transport experiments were performed by the rapid centrifugation method.


RESULTS
In an in vitro cytotoxicity experiment, M5076 cells showed lower sensitivity to DOX than to THP, and the cytotoxicity of THP and DOX toward M5076 cells was lower than toward Ehrlich cells, and these results were similar to those of an in vivo experiment. This was due to the much lower expression of topoisomerase II in M5076 cells than in Ehrlich cells. The amount of intracellular DOX was found to be significantly lower than that of THP in both cell types, and furthermore, little free intracellular DOX was observed in M5076 cells, indicating that the low sensitivity of M5076 cells to DOX was partially a result of the low amount of intracellular DOX. There was no difference in the efflux rate, but there was an apparent difference in the uptake efficiency of the carrier between THP and DOX.


CONCLUSIONS
These findings suggest that the cytotoxicities of THP and DOX toward M5076 and Ehrlich cells depend, at least in part, on the uptake efficiency of the carrier.
Nagai
Katsuhito
K
Department of Environmental Biochemistry, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
Nagasawa
Kazuki
K
Sadzuka
Yasuyuki
Y
Tsujimoto
Masayuki
M
Takara
Kohji
K
Ohnishi
Noriaki
N
Yokoyama
Teruyoshi
T
Fujimoto
Sadaki
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects*; D004140:Dinitrophenols / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D004140:Dinitrophenols; D004317:Doxorubicin; C027260:pirarubicin