Correlations between the activities of 19 anti-tumor agents and the intracellular glutathione concentrations in a panel of 14 human cancer cell lines: comparisons with the National Cancer Institute data

Abstract

The aim of this work was 2-fold: (i) to identify correlations between the activities of pairs of 19 anti-tumor agents in a mini-panel of 14 human cancer cell lines of diverse origins with the goal of validating the panel, and (ii) to look for correlations between the activities of 19 standard anti-tumor agents and the intracellular concentrations of glutathione (GSH). Validation with analogous data from the National Cancer Institute (NCI) Developmental Therapeutics Program was made. The cell growth inhibition potencies of the anti-tumor agents [cisplatin, carboplatin, oxaliplatin, DACH-Pt, melphalan, chlorambucil, thiotepa, busulfan, doxorubicin, etoposide, camptothecin, vinblastine, podophyllotoxin, colchicine, taxol, hydroxyurea, methotrexate, 5-azacytidine and 5-fluorouracil (5-FU)] were estimated in 14 cancer cell lines by their GI50 values. An enzymatic assay based on the method of Tietze was employed to measure intracellular total GSH concentrations. The Delta method was used to compare pairs of anti-tumor agents; similarities and differences in activity profiles (mean graphs) were evaluated by regression analysis. Most, but not all, of the correlations could be explained based on similarities in the mechanisms of action and many correlations/non-correlations were also observed in the NCI data. Some correlations were unexpected however, and not seen in the NCI data. For example, strong positive correlations (P < 0.01) were found between the GI50 values of melphalan/chlorambucil and the anti-mitotic agents. Similarly unexpected, a strong positive correlation was observed between methotrexate and cisplatin (P < 0.01). Interestingly, moderate to strong negative correlations (P < 0.01-0.05) were found between the GI50 values of 5-FU and the anti-mitotic agents/melphalan/chlorambucil. Significant positive correlations between intracellular GSH concentrations and GI50 values were found only for thiotepa (P < 0.05) and doxorubicin (P < 0.01). Data from a NCI panel of 34 cancer cell lines showed no correlations between GSH levels and the GI50 values of the same 19 compounds. In conclusion, a panel of 14 human cancer cell lines of diverse origin was used to identify similarities and differences in the activities of standard anti-tumor agents. The level of significance was stronger with the 34 cell lines of the NCI, however. Our results indicate that GSH intracellular concentrations correlate with resistance only with doxorubicin and thiotepa in these cell lines.

Topoisomerase IIα-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin

“…A major portion of doxorubicin-induced apoptosis in HTETOP cells appears to be triggered by a pronounced depletion of total cellular glutathione. Glutathione depletion by doxorubicin has been reported in a recent study (29) and intracellular glutathione levels are remarkably specific predictors of doxorubicininduced cell growth inhibition (30). The glutathione depletion could be caused by outward cotransport of doxorubicin and glutathione by the multidrug resistance protein 1 (31) or by inhibition of glutathione synthesis (23).…”

Effects of light-activated diazido-PtIVcomplexes on cancer cellsin vitro

“…In a panel of 13 human cancer cells lines, an average IC 50 value of 55 ± 28 µM (range 29-139 µM) after 30 min irradiation (0.12 mW cm −2 ) was found for 4 when photoactivated with UVA, although visible light was also effective [23]. The selectivity towards this panel of cell lines was far less than for cisplatin, which averages an IC 50 of 1.36 ± 1.28 µM (range 0.24-4.09 µM) for the same panel of lines [35]. Thus, not only is the potency of light-activated 4 less than cisplatin, the cytotoxicity is also less specific.…”

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]

“…[34] However, carboplatin shows reduced side-effects compared to cisplatin, making it a useful therapy for cancer. Thus, not the absolute potency is critical for anticancer activity but rather width of the therapeutic index, and light activated platinum complexes would be expected to have a wider therapeutic index than platinum complexes that are not selectively activated.…”