Evaluation of the cytotoxicity of selected systemic and intravitreally dosed drugs in the cultures of human retinal pigment epithelial cell line and of pig primary retinal pigment epithelial cells

Mannerström, Marika; Zorn-Kruppa, Michaela; Diehl, H.; Engelke, Maria; Toimela, Tarja; Mäenpää, Hanna; Huhtala, Anne; Uusitalo, Hannu; Salminen, Leena; Pappas, Periklis; Marselos, Marios; Mäntylä, M.; Mäntylä, Eero; Tähti, Hanna

doi:10.1016/s0887-2333(01)00113-8

Cited by 29 publications

(21 citation statements)

References 23 publications

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“…WST-1 reflects the metabolic state of cells. In our earlier studies (Mannerstro¨m et al 2002;Toimela and Ta¨hti 2001) we have seen an increase of enzyme activity in connection with WST-1 test. This study showed the same phenomenon, especially at low concentrations of aluminum and methylmercury.…”

Section: Discussionmentioning

confidence: 62%

Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin

Toimela

Tähti

2004

Arch Toxicol

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Mercury and aluminum are considered to be neurotoxic metals, and they are often connected with the onset of neurodegenerative diseases. In this study, mercuric mercury, methylmercury and aluminum were studied in three different cell lines of neural origin. To evaluate the effects, mitochondrial cytotoxicity and apoptosis induced by the metals were measured after various incubation times. SH-SY5Y neuroblastoma, U 373MG glioblastoma, and RPE D407 retinal pigment epithelial cells were subcultured to appropriate cell culture plates and 0.01-1,000 microM concentrations of methylmercury, mercuric and aluminum chloride were added into the growth medium. In the assay measuring the mitochondrial dehydrogenase activity, WST-1, the cultures were exposed for 15 min, 24 or 48 h before measurement. Cells were allowed to recover from the exposure in part of the study. Apoptosis induced by the metals was measured after 6-, 24- and 48-h exposure times with the determination of activated caspase 3 enzyme. Mitochondrial assays showed a clear dose-response and exposure time-response to the metals. The most toxic was methylmercury (EC50 ~0.8 microM, 48 h), and the most sensitive cell line was the neuroblastoma cell line SH-SY5Y. Furthermore, there was marked mitochondrial activation, especially in connection with aluminum and methylmercury at low concentrations. This activation may be important during the initiation of cellular processes. All the metals tested induced apoptosis, but with a different time-course and cell-line specificity. In microscopic photographs, glioblastoma cells formed fibrillary tangles, and neuroblastoma cells settled along the fibrilles in cocultures of glial and neuronal cell lines during aluminum exposure. The study emphasized the toxicity of methylmercury to neural cells and showed that aluminum alters various cellular activities.

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Section: Discussionmentioning

confidence: 62%

Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin

Toimela

Tähti

2004

Arch Toxicol

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“…However, it is not possible to assess whether a BrdU+ cell has just been labeled or is a descendant of a previously labeled cell. It is not known if epithelial stem/progenitor cells show the same behavior against 5-FU like hematopoietic stem cells, although it is reported that 5-FU does eliminate proliferating epithelial cells such as retinal pigment epithelial cells [28] and lens epithelial cells [29]. Our data support the concept that a small pool of cells in the distal region of S3 may divide once after injury and then retain the label for a prolonged period of time, suggesting that these cells may in some way be unique.…”

Section: Discussionmentioning

confidence: 99%

A Distinct Population of Tubular Cells in the Distal S3 Segment Contributes to S3 Segment Regeneration in Rats following Acute Renal Failure Induced by Uranyl Acetate

Sakakima

Fujigaki²,

Yamamoto³

et al. 2008

Nephron Exp Nephrol

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Background: We previously reported that early regenerating cells found at the distal area of the S3 segment of the nephron (designated as target cells) were label-retaining cells in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. In this study, we examined the contribution of these target cells to S3 segment repair after UA treatment. We also discriminated target cells from bromodeoxyuridine (BrdU)-label-retaining cells labeled under normal conditions and examined their capacity to proliferate following a second insult and their resistance to 5-fluorouracil (5-FU). Methods: Target cells were labeled and tracked using a ³H-thymidine pulse/chase approach after UA (4 mg/kg) injection to rats. Normal rats were labeled with BrdU, and cells positive for BrdU and Ki67 were analyzed after UA treatment. The kinetics of target cells was examined after a second dose of UA and treatment with 5-FU. Results: The target cells were strongly labeled by ³H-thymidine and were predominantly found in the distal quarter of the S3 segment until 40 weeks after generating ‘label-diluted’ cells throughout the S3 segment. Cells labeled with BrdU under normal conditions did not express Ki67 after UA treatment but target cells were Ki67-positive. The target cells underwent further proliferation following the second treatment with UA and were transiently arrested by 5-FU treatment at G0/G1 after UA. Conclusions: The target cells are slow-cycling cells, resistant to 5-FU treatment and have the capacity to undergo further proliferation following a second insult with UA. These data suggest the presence of a distinct population of cells that can regenerate the S3 segment in UA-induced ARF.

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“…Dose-related increases in micronuclei were observed when cells expressing 2E1, 3A4, 2D6 or MCL-5 cells were exposed to tamoxifen (Styles et al 1997). The cytotoxicity of the tamoxifen has been investigated in the RPE cell line D407 and pig RPE cell culture using the WST-1 test, which is an assay of cell proliferation and viability (Mannerström et al 2002). Tamoxifen was found cytotoxic in this test system.…”

Section: Genotoxicitymentioning

confidence: 99%

“…Okuboa et al (1998) reported that toremifene and N-desmethyltoremifene did not cause damage in pUC18 plasmid DNA. The cytotoxicity of toremifene has been investigated in RPE cell line D407 and the pig RPE cell culture using the WST-1 test (Mannerström et al 2002). Toremifene was found cytotoxic in these test systems.…”

Section: Toremifenementioning

confidence: 99%

“…Leukocytes were collected from 27 breast cancer patients taking toremifene (40 mg/day for 25 patients, Williams, and Jeffrey (1997), White (1999), Rajaniemi et al (1998a, b), Hellmann-Blumberg et al (2000) pUC18 plasmid DNA DNA damage - Okuboa et al (1998) RPE cell line D407, pig RPE cell culture WST-1 test ? Mannerström et al (2002) ? : Positive, -: Negative Cytotechnology (2014) 66:533-541 537 80 mg/day for one patient, and 120 mg/day for one patient) and 20 untreated breast cancer patients.…”

Section: Toremifenementioning

confidence: 99%

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Genotoxicity of the some selective estrogen receptor modulators: a review

2014

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The objective of this article is to review genotoxicological profile of the major selective estrogen receptor modulators, including clomiphene, tamoxifen, toremifene, raloxifene. These drugs have been used for infertility treatment and breast cancer prevention in high risk-women. However, some studies reported that especially tamoxifen is a genotoxic agent and is related with endometrial cancer. Our review indicate that clomiphene and tamoxifen were found as genotoxic agent in majority of the tests. However published reports showed that toremifene is a weakly genotoxic agent. The genotoxic effects of raloxifene are still poorly known. Further genotoxicity studies should be conducted especially for raloxifene.

show abstract

Evaluation of the cytotoxicity of selected systemic and intravitreally dosed drugs in the cultures of human retinal pigment epithelial cell line and of pig primary retinal pigment epithelial cells

Cited by 29 publications

References 23 publications

Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin

Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin

A Distinct Population of Tubular Cells in the Distal S3 Segment Contributes to S3 Segment Regeneration in Rats following Acute Renal Failure Induced by Uranyl Acetate

Genotoxicity of the some selective estrogen receptor modulators: a review

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