Biomedical subjects

S M Sharkey

Publications and source records attributed to S M Sharkey.

4 recordsLinked to original sources

PubMed1993

Mitochondrial alterations in photodynamic therapy-resistant cells.

The characterization of radiation-induced fibrosarcoma cells (RIF-8A) which have been selected for resistance to Photofrin-mediated photodynamic therapy (PDT) is detailed in this report. Morphological and functional assessment of mitochondria in both the resistant RIF-8A and parental RIF-1 cells show distinct differences. Electron micrographs show that the mitochondria in the RIF-8A cells are relatively smaller; stain more densely, and display a higher cristae density than RIF-1 cells. P. A. Andrews et al. (Cancer Res., 52: 1895-1901, 1992) reported similar mitochondrial differences between a human ovarian carcinoma cell line, 2008, and its cisplatin-resistant counterpart (C13*). Dose-response curves demonstrate that these cisplatin-resistant C13* cells show cross-resistance to Photofrin-mediated PDT. Functionally, the RIF-8A cells produce more ATP and demonstrate higher succinate dehydrogenase activity than do the RIF-1 cells, but the rates of oxygen consumption do not differ between the two cell types. The PDT-sensitive RIF-1 cells demonstrate a significantly higher susceptibility to inhibition of glycolytic activity as determined by 2-deoxy-d-glucose survival curves. These findings suggest differences in the efficacy and/or mode(s) of energy production in the RIF-1 and RIF-8A cells. Since mitochondria are sensitive targets for porphyrin-mediated PDT, the observed changes in mitochondrial structure and/or function may be involved in the PDT resistance seen in RIF-8A cells.

Adenosine Triphosphate↗

PubMed1992

Mitochondrial DNA damage by anticancer agents.

Mitochondrial DNA (mtDNA) is susceptible to damage by a number of anticancer agents either directly or indirectly. This damage is of little consequence if only a few of the mtDNA molecules are damaged. However, multiple drug treatments could result in a significant effect on a cell's ability to survive. The differential effect of anticancer agents on either organ specific toxicities or selective tumor kill can be partially accounted for by differential mtDNA content of cells and on the basis of differential protective mechanisms within mitochondria of various organs or tumor tissue. The concept of damage to mitochondria, especially its genome, is a subject of active investigation in various laboratories. This area of research may provide mechanism(s) by which organ specific toxicities or tumor specific toxicities may be elaborated. Also, the concept of targeting tumor specific mitochondria and/or mtDNA by anticancer agents is very attractive but has not come to fruition due to a lack of understanding of the regulation of the genome in tumor cells. Future investigations in this arena will enhance our knowledge on the interaction between anticancer agents and extranuclear DNA.

Animals↗

PubMed1991

Resistance to photodynamic therapy in radiation induced fibrosarcoma-1 and Chinese hamster ovary-multi-drug resistant. Cells in vitro.

A degree of resistance to photodynamic therapy (PDT) has been induced in radiation-induced fibrosarcoma-1 (RIF-1) tumor cells by repeated photodynamic treatment with Photofrin (4 or 18 h incubation) in vitro to the 0.1-1% survival level, followed by regrowth from single surviving colonies. The resistance is shown as increased cell survival in the strain designated RIF-8A, compared to the wild-type RIF-1 cells, when exposed to increasing Photofrin concentration for 18 h incubation and fixed light exposure. No difference was found between RIF-1 and RIF-8A in the uptake of Photofrin per unit cell volume at 18 h incubation. Resistance to PDT was also observed in Chinese hamster ovary-multi-drug resistant (CHO-MDR) cells compared to the wild-type CHO cells, possibly associated with decreased cellular concentration of Photofrin in the former. By contrast, the PDT-resistant RIF-8A cells did not show any cross-resistance to Adriamycin, nor was there any significant drug concentration difference between RIF-1 and RIF-8A. These findings suggest that different mechanisms are responsible for PDT-induced resistance and multi-drug resistance.

Animals↗

PubMed1986

Quantitation of nuclear aberrations as a screen for agents damaging to mammary epithelium.

The early nuclear damage caused by two known breast carcinogens, radiation and 7,12-dimethylbenzanthracene (DMBA), was quantitated by scoring for nuclear aberrations in mammary epithelium. Seven-week-old C57BL/6J female mice were irradiated with whole body gamma radiation or were given various doses of DMBA. The terminal end buds and ducts were separated and processed for histological preparation. The number of nuclear aberrations per 1000 cells was scored from coded slides. Animals receiving no treatment had a low level of these figures in their terminal end buds (34 +/- 7/1000 cells) but the number increased in a dose-related manner to a maximum of 161 +/- 20/1000 cells when they were treated with 8 Gy. Apoptosis in the ductal epithelium was much less frequent than in the terminal buds and the quantitation of nuclear aberrations from these structures was a less sensitive and reliable indicator of damage. DMBA and N-nitroso-N-methylurea are breast carcinogens from the polycyclic aromatic hydrocarbon and nitroso classes respectively. These chemicals cause increases in the nuclear aberration incidence in the terminal end buds but related carcinogens with different target specificities and noncarcinogens do not appear to produce such elevations. These results suggest that the quantitation of nuclear aberrations in breast epithelium might be used as a short-term, tissue-specific screen for breast carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗