This project is based upon our original observation that sulfhydryl (SH) compounds potentiate the inhibitory effect of selenite on the activity of DNA and RNA polymerases. We originally proposed to investigate the mechanism of this effect, and its relevance to the inhibition by selenite of DNA and RNA synthesis in the cell. During the past project period we have shown that inhibition of the polymerases results form the reaction of selenite with the SH compounds to form selenotrisulfides. In the case of RNA polymerase II, inhibition is limited to the initiation stage of the reaction. We have also found that upon exposure of the polymerases to selenotrisulfidesa Se-protein adduct is formed. During the next project period we will investigate the structure of the adduct and the specificity of its formation at different stages of the RNA polymerase II reaction. During the past project period we examined the effect of depleting cells of SH compounds on the inhibitory effect of selenite on nucleic acid synthesis. The result have provided direct evidence for the involvement of cellular SH compounds in the inhibition by selenite of DNA and RNA synthesis in living cells. Our results have dictated, however, that the predominant cellular SH compound, glutathione, is not involved in this effect. Dung the next project period we will examine the intracellular fate of exogenous selenite in order to determine which cellular SH compounds are involved. We will also examine the possible involvement of SH compounds in the inhibition by selenite of cell proliferation and cell transformation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004087-06
Application #
3251989
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1986-06-15
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Rutgers University
Department
Type
Schools of Arts and Sciences
DUNS #
130029205
City
Newark
State
NJ
Country
United States
Zip Code
07102
Caffrey, P B; Frenkel, G D (2000) Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo. Cancer Chemother Pharmacol 46:74-8
Caffrey, P B; Zhu, M; Zhang, Y et al. (1999) Rapid development of glutathione-S-transferase-dependent drug resistance in vitro and its prevention by ethacrynic acid. Cancer Lett 136:47-52
Caffrey, P B; Zhang, Y; Frenkel, G D (1998) Rapid development of drug resistance in human ovarian tumor xenografts after a single treatment with melphalan in Vivo. Anticancer Res 18:3021-5
Zhu, M; Gong, Y; Frenkel, G D (1998) Studies on the mechanism of the selenite-induced decrease in cell attachment: effect of selenite on the levels of fibronectin receptor (alpha5beta1 integrin) mRNAs. Biol Trace Elem Res 62:123-34
Caffrey, P B; Frenkel, G D (1998) Treatment of human ovarian tumor xenografts with selenite prevents the melphalan-induced development of drug resistance. Anticancer Res 18:3017-20
Caffrey, P B; Zhu, M; Frenkel, G D (1998) Prevention of the development of melphalan resistance in vitro by selenite. Biol Trace Elem Res 65:187-95
Caffrey, P B; Frenkel, G D (1997) Sensitivity of melphalan-resistant tumors to selenite in vivo. Cancer Lett 121:177-80
Yan, L; Frenkel, G D (1994) Protein synthesis is not required for the inhibitory effect of selenite on cell colony formation and RNA synthesis. Biol Trace Elem Res 40:181-7
Yan, L; Frenkel, G D (1994) Effect of selenite on cell surface fibronectin receptor. Biol Trace Elem Res 46:79-89
Caffrey, P B; Frenkel, G D (1994) The development of drug resistance by tumor cells in vitro is accompanied by the development of sensitivity to selenite. Cancer Lett 81:59-65

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