The role of apoptosis in cell killing by cisplatin: a flow cytometric study

Ormerod, M.G.; Orr, Rosanne M.; Peacock, J.H.

doi:10.1038/bjc.1994.14

Cited by 129 publications

(75 citation statements)

References 38 publications

(34 reference statements)

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“…Similar cell cycle perturbations were observed with cisplatin in each cell line and in the CH1 cell line with JM149 and JM335 , and are consistent with the observations of other authors (Vaisman et al, 1997;Zaffaroni et al, 1998). Taken together these and other studies indicate that accumulation of cells in S phase, is a general cell cycle effect of platinum drugs, which depending on the cell type, is associated with G2 arrest (Ormerod et al, 1994bO'Neill et al, 1996;Vaisman et al, 1997;Zaffaroni et al, 1998). In the CH1 cell lines, accumulation of cells in G2 coincided with the point at which significant apoptosis was occurring.…”

Section: Discussionsupporting

confidence: 91%

“…In the CH1 cell lines, accumulation of cells in G2 coincided with the point at which significant apoptosis was occurring. It has been suggested that G2 arrest facilitates repair of DNA damage prior to mitosis and depending on the success of repair or extent of DNA damage, cells emerging from G2 either begin to cycle normally or engage apoptosis (Sorenson and Eastman, 1988;Ormerod et al, 1994b). Our data suggests that the latter may be occurring in the CH1 cell lines, despite the repair of Pt lesions induced by JM216.…”

Section: Discussionmentioning

confidence: 56%

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Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin

O’Neill¹,

Koberle²,

Kèlland³

1999

Br J Cancer

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Summary JM216, an oral platinum drug entering into phase III clinical trial, exhibited comparable cytotoxicity to cisplatin in three human ovarian carcinoma cell lines: the sensitive (CH1), acquired resistant (CH1cisR) and intrinsically resistant (SKOV-3). Platinum accumulation and binding to DNA were similar in each of the three cell lines at equimolar doses, indicating that the resistant cell lines could tolerate higher intracellular platinum levels and platinum bound to DNA at IC 50 concentrations of drug. Comparison with cisplatin demonstrated that intracellular platinum levels were marginally higher with JM216, but that platinum binding to DNA was similar for the two drugs in each of the cell lines. Each of the cell lines exhibited an ability to repair JM216 induced platinum/DNA lesions in the N-ras gene (gene-specific repair) at equitoxic concentrations of drug. However, this occurred to a greater extent in the two resistant cell lines such that by 24 h the CH1cisR and SKOV-3 had removed 72% and 67% respectively compared with approximately 32% for the CH1. Reduced gene-specific repair capacity in CH1 cells was also seen following incubation with 25 µM (or 5 µM -2 × IC 50 ) cisplatin, whereas the CH1cisR and SKOV-3 cell lines were repair proficient. JM216 induced apoptosis in the three cell lines following a 2h incubation with 2 × the IC 50 of drug. Fluorescent microscopy of cells stained with propidium iodide showed that the detached cell population displayed typical apoptotic nuclei. Furthermore, field inversion gel electrophoresis demonstrated the presence of DNA fragments approximately 23-50 kb in size, indicative of apoptosis, in the detached cells. JM216 induced an S phase slow down in each of the three cell lines accompanied by a G2 block in the CH1 pair. Incubation with this concentration of JM216 also resulted in the induction of p53 in the CH1 and CH1cisR. These studies suggest that the relative sensitivity of the CH1 cell line to cisplatin and JM216 is at least partly attributable to a deficiency in gene-specific repair. The oral platinum drug, JM216, exerts its cytotoxic effects through the induction of apoptosis following a slow-down in S phase in both the sensitive and resistant lines.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 56%

Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin

O’Neill¹,

Koberle²,

Kèlland³

1999

Br J Cancer

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“…At supralethal concentrations of cisplatin (100 gM), rapid apoptotic death occurred in a murine leukaemic cell line, whereas lower concentrations (1-10 tM) caused G2 arrest followed by slow non-apoptotic death (Ormerod et al, 1994). Others have shown that, in human lymphoblastoid cells, DNA damage by cisplatin may result in p53-mediated apoptosis of cells in G,/S-phase or p53-independent apoptosis of p53 mutant cells in G2/M-phase of the cell cycle (Allday et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro

Armour

Cunningham²,

Gaze³

et al. 1997

Br J Cancer

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Summary [1311]meta-iodobenzylguanidine ([1311]MIBG) provides a means of selectively delivering radiation to neuroblastoma cells and is a promising addition to the range of agents used to treat neuroblastoma. As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 giM

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“…The drug causes platination of DNA (Roberts and Thomson, 1979) which leads to inter and intrastrand cross-linking (Eastman, 1985(Eastman, , 1987. As a result the rate of DNA synthesis is reduced and often cells become arrested in the G2/M stage of the cell cycle (Ormerod et al, 1994). Several studies have demonstrated that certain tumor-derived cell lines exposed to high doses of cisplatin die by apoptosis which is preceded by the induction of p53 protein in a dose dependent manner (Allday et al, 1995a;Zhang et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Human lymphoblastoid cell lines expressing mutant p53 exhibit decreased sensitivity to cisplatin-induced cytotoxicity

1998

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Human lymphoblastoid cells were transfected with expression vectors containing p53 cDNA mutated at either codon 135 or 246. The cells were subjected to cisplatin treatment or g-radiation and observed for changes in the cell cycle arrest and apoptosis. We found that compared to the parental cell line, cells overexpressing mutant p53 (either 246 val or 135 ser ) exhibited decreased apoptosis in response to g-radiation or cisplatin as measured by: propidium iodide (PI) staining of the cellular DNA (cell cycle analysis) and decrease in PARP (poly ADP-ribose polymerase) cleavage as detected by Western blotting. Interestingly the cells expressing mutant p53(135 ser ) protein were less resistant to cisplatin-induced apoptosis than the p53(246 val )-bearing cell line. A signi®cant decrease in the G1/S arrest assayed by bromodeoxyuridine and PI staining (cell cycle/proliferation assay) was also observed in response to irradiation and cisplatin in cell lines expressing either of the mutant p53 constructs. A lower basal level and reduced magnitude of protein induction of the cell cycle inhibitor p21/Waf1 was seen both after cisplatin and g-radiation treatment in the mutant p53 expressing lymphoblastoid variant when compared to the wild type p53 parental cell line but induction of the p53 regulator MDM2 was comparable in both. No increase in basal levels of Bc12 protein in wild type or mutant p53 expressing cells was observed in response to cisplatin or irradiation. Unexpectedly, following cisplatin treatment we observed an increase in mutant and wild type p53 RNA steady state levels in addition to increased levels of p53 protein. These results suggest that irradiation or cisplatin treatment may not only stabilize wild type p53 protein but also may increase the steady state p53 RNA levels. Finally these results indicate that both irradiation and cisplatin should be used with caution in the treatment of lymphoid tumors bearing mutations of p53.

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The role of apoptosis in cell killing by cisplatin: a flow cytometric study

Cited by 129 publications

References 38 publications

Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin

Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro

Human lymphoblastoid cell lines expressing mutant p53 exhibit decreased sensitivity to cisplatin-induced cytotoxicity

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