5-Fluorouracil (FUra)

Valeriote, Fred; Santelli, Giovanni

doi:10.1016/0163-7258(84)90030-5

Cited by 75 publications

(26 citation statements)

References 69 publications

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“…Hypoxia-induced ADR resistance has been proposed to be related to the depletion of topoisomerase II which has been observed to be caused by hypoxia or glucose starvation . However, this hypothesis is not likely to explain the development of hypoxia-induced resistance to 5-FU, because the mechanism of action of 5-FU does not directly involve topoisomerase II (Valeriote & Santelli, 1984). Two observations may explain this observed resistance to 5-FU.…”

Section: Methodsmentioning

confidence: 73%

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance

Sakata

Kwok²,

Murphy³

et al. 1991

Br J Cancer

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Summary In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance.As a tumour grows, heterogeneities of cellular microenvironments occur, such as the development of oxygen gradients in the tumour as a consequence of deficient vascularisation, and cause hypoxic cells that may be resistant to radiotherapy (Sutherland, 1988). Several studies using monolayer cultures (Smith et al., 1980;Teicher et al., 1981Teicher et al., , 1985 and the multicell spheroid system (Sutherland et al., 1979) Conditions of hypoxic exposure Before being gassed with N2, the cells were supplied with 5 ml of fresh complete medium and allowed to equilibrate in a humidified 37°C incubator. Cells undergoing hypoxic stress were isolated in specially designed hypoxic chambers at room temperature (Sutherland et al., 1982). The chambers were repeatedly evacuated and filled every 15 min for 2.25 h with the appropriate gas mixtures certified to contain less than 10 ppm 02. The sealed chambers were then removed to a warm room (37'C) at a time point, t, referred to hereafter as '0' hours of hypoxia.Preparation of drugs and conditions of drug exposure All drugs used were obtained from Sigma Chemical Company. Stock solutions of adriamycin (ADR), vincristine, and actinomycin D (ACTD) were prepared with phosphatebuffered saline (PBS). Solutions of 5-fluorouracil (5-FU), colchicine, and cisplatin were made before each experiment. The solvents used were PBS for ADR, ACTD and cisplatin and distilled water for 5-FU. Absolute ethanol was used as a solvent for colchicine in order to obtain a sufficiently high concentration for the experiments. The final concentration of alcohol in the medium was 1%. As a control for the alcohol solvent, we established that 1% of absolute ethanol in cultures for 2 h had no effect on plating efficiency. Drug treatment was started under aerobic conditions at 37'C in the incubator after culture dishes were removed from the chambers at the zero time. Exposure times for ADR, ACTD and cisplatin were 1 h. A 2 h exposure time was used for 5-FU, colchicine and vincristine to cause significant cell killing. Exposure times were limited to 1-2 h to avoid the effect of release from a ORPs-induced state,...

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Section: Methodsmentioning

confidence: 73%

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance

Sakata

Kwok²,

Murphy³

et al. 1991

Br J Cancer

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“…There are three main theories: 1) Inactivation of thymidylate synthetase prevents de novo synthesis of dTMP resulting in inhibi-tion of the DNA synthesis (9,16,18,19,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) (3,6,13,14,27). Based on our results, it may be possible to explain the immediately depressed DNA synthesis rate by an inactivation of thymidylate synthetase.…”

Section: Discussionmentioning

confidence: 99%

Effect of 5-Fluorouracil on the Cell Growth and Cell Cycle Kinetics of a Mouse Ascites Tumor Growing in Vivo

et al. 1987

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“…While 100% remissions were obtained with certain therapeutic schedules at day 30, some animals treated with the same schedules still died within 5 months of follow-up. This can be explained by the fact that cavitation, as well as FUra, induces a blockade of the cell cycle and an accumulation of cells in GO/GI (Prat et al, personal communication;Valeriote & Santelli, 1984); we thus suggest that some cancer cells, still present in the peritoneum at day 30, may re-enter the cell-cycle or continue tumour growth at a slower rate.…”

Section: Animalsmentioning

confidence: 99%

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mentioning

confidence: 99%

In vivo effects of cavitation alone or in combination with chemotherapy in a peritoneal carcinomatosis in the rat

Prat

Chapelon²,

Fadil³

et al. 1993

Br J Cancer

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Summary Cavitation (volume oscillations and collapse of gas bubbles), as generated by a co-administration of shockwaves (SW) and microbubbles (SWB) Group, 1984;Calabresi & Chabner, 1990;Valeriote & Santelli, 1984) and only surgery is able to improve survival in less than 10% of the patients with liver metastasis (Nakamura et al., 1992;Registry of Hepatic Metastases, 1988). New therapeutic instruments are thus clearly needed to improve the prognosis of metastasis from bowel malignancies. Despite disappointing results from radiotherapy and conventional hyperthermia, physical methods may be interesting as an alternative approach to, or in combination with, chemotherapy. Biological effects of acoustic waves, like high intensity ultrasound and shock waves have been studied for many years (Flynn, 1964;Church & Miller, 1983); while direct cytotoxic effects may play a minor role, several studies have shown that damage is caused to microvessels and endothelial cells, causing vascular disruption as well as the production of free radicals, leading to hypoxia and indirect toxicity to the affected tissue (Miller, 1987). It has also been demonstrated that the cytotoxicity of shock waves was obtained mostly through acoustic cavitation, which is the transitory volume oscillations of gas microbubbles induced by rapidly varying pressure waves, eventually resulting in the collapse of bubbles (Dear et al., 1988). When a bubble collapses near an interface with a cell membrane, such dramatic damage is inflicted to the cell as to induce cell death (Delius et al., 1989;Miller, 1987;Miller et al., 1991). However, the therapeutic potentialities of cavitation have so far remained confined to in vitro experimental studies and have not evolved toward clinical applications for two reasons: (1) ultrasound was not able to induce cytotoxicity unless generated in vitro in specific experimental conditions (Church & Miller, 1983); (2) (Prat et al., 199 la). Further experiments with HT-29 cells in suspension and viable rat colon peritoneal metastases treated in vitro showed that cavitation could hinder cell proliferation and induce complete tissue necrosis (Prat et al., 1991b). In a more recent study (Prat et al., personal communication), the cytotoxicity of FUra to HT-29 cells was greatly enhanced by a preliminary exposure of the cells to cavitation, through potentially synergistic mechanisms.In the present study, we aimed at investigating the relevance of cavitation to the treatment of a disseminated digestive tumour in vivo. Materials and methodsCells DHD K12 PROb cells (a gift from Pr Martin, INSERM U252, Dijon, France) originated from a dimethyl-hydrazineinduced rat colon carcinoma were cultured in Dulbecco's modified Eagle's medium supplemented with 8% fetal calf serum under 8% CO2. The cells were cultured to confluence in 75 cm2 flasks and detached after 12 days of culture by 2.5/1000 trypsin/0.2/1000 EDTA. Cell viability was assessed before each use by trypan blue exclusion; it was always over 90%. AnimalsMale and female BD IX rats, syng...

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5-Fluorouracil (FUra)

Cited by 75 publications

References 69 publications

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance

Effect of 5-Fluorouracil on the Cell Growth and Cell Cycle Kinetics of a Mouse Ascites Tumor Growing in Vivo

In vivo effects of cavitation alone or in combination with chemotherapy in a peritoneal carcinomatosis in the rat

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