| Autor: |
Doroshow JH; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.; Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.; Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center , Duarte , CA , USA., Juhasz A; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , MD , USA.; Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center , Duarte , CA , USA. |
| Abstrakt: |
To define the role of glutathione peroxidase (GPx) in modulating the oxygen radical-related cytotoxicity of doxorubicin and H 2 O 2 in cells that overexpress P-glycoprotein (Pgp), the GPx activity of NCI/ADR-RES cancer cells was altered by growth in 0.5% serum with (MR-30 subline) or without (MR-0 subline) selenium supplementation. GPx activity increased from 2.2 nmol/min/mg (MR-0) to 22.5 nmol/min/mg (MR-30) when cells were grown in 30-nM selenium, p < .01; the activities of other antioxidant enzymes were unchanged by selenium. By reverse transcriptase polymerase chain reaction, MR-30 and MR-0 cells expressed similar levels of the MDR 1, GPx-1, BCL2 and TOP2A mRNA. The IC 50 concentration for H 2 O 2 in MR-0 cells was 10-fold lower than in the MR-30 subline, p < .01. Despite identical anthracycline accumulation and efflux in these two lines that expressed equivalent levels of Pgp, the doxorubicin IC 50 decreased fivefold in MR-0 versus MR-30 cells, p < .01. Log-linear tumour cell killing by doxorubicin was observed only in selenium-deficient MR-0 cells. Doxorubicin exposure also produced substantially more apoptosis in MR-0 than MR-30 cells; this was not related to the presence of selenium per se . MR-0 cells generated ≈5-times more methane from dimethyl sulfoxide (a measure of reactive oxygen metabolism) than MR-30 cells in the presence of equimolar doxorubicin concentrations ( p < .05). These studies suggest that GPx-mediated detoxification of peroxides can modulate the antitumor activity of doxorubicin in the presence of high levels of Pgp. |
