抄録
The succinate dehydrogenase inhibition (SDI) test and human tumor clonogenic assay (HTCA) have some methodological differences. However, the effects that these differences have on cytotoxicity estimates of antineoplastic agents have not been rigorously examined. To re-examine the SDI test, the AUC (area under the concentration-time curve) values producing 50% inhibition of cisplatin (CDDP), carboplatin (CBDCA) and mitomycin C (MMC) in the conventional SDI test, without a drug-free incubation period after drug-exposure; the modified SDI test, with a drug-free incubation period; and the HTCA using a panel of PC-7, PC-9, PC-14 and K562 cells were compared with that of respective AUC in clinical pharmacokinetics. DNA histograms determined by flow cytometry using propidium iodide were estimated for cells during the drug-free incubation. CDDP, CBDCA and MMC were all confirmed to have AUC dependent cytotoxicity. The AUC50/AUCclin. ratio for MMC as determined by the conventional SDI, were significantly higher in all four cell lines than those for CDDP and CBDCA. While, in the modified SDI, the AUC50/AUCclin. values were decreased and in agreement with those obtained by the HTCA. In the DNA histogram after the drug-free incubation, MMC showed the most cytotoxic change, which was a severe decrease in G1 and G2 phase and increased fragmented particles indicating apoptosis. Drugs with strong cytotoxicity that persists after exposure, such as MMC, are underestimated with respect to their cytotoxicity when the conventional SDI test without a drug-free incubation is used.
