Relationship of Mitotic Arrest and Apoptosis to Antitumor Effect of Paclitaxel

Milross, Christopher G.; Mason, Kathryn A.; Hunter, Nancy; Chung, Won Jee; Peters, Lester J.; Milas, Luka

doi:10.1093/jnci/88.18.1308

Cited by 253 publications

(140 citation statements)

References 30 publications

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“…45 Surprisingly, Taxol was largely ineffective at inducing apoptosis in these same gastric tumor cells when they were blocked at later phases of the cell cycle by stage-specific drugs, 45 even though Taxol is expected to cause phase arrest at the G 2 /M phase. 46 Because GCV has been reported to lead to cell cycle arrest between late G 1 and early G 2 phases, 11,12,17 our results with GCV and Taxol combinations are consistent with the reported ineffectiveness of Taxol in gastric cells arrested beyond the early G 1 phase. 45 Also, GCV plus another microtubule inhibitor, vinblastine, yielded effects that were similar to those observed with Taxol/GCV (data not shown).…”

Section: Discussionsupporting

confidence: 77%

Two-drug combinations that increase apoptosis and modulate Bak and Bcl-XL expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase

et al. 2000

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Herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) gene therapy can induce apoptosis in tumor cells that are normally resistant to this type of cell death, although the cellular mechanisms by which this occurs remain to be elucidated. Human colon tumor cell lines expressing HSV-TK were treated with GCV or four other inducers of apoptosis: butyrate, camptothecin (CPT), Taxol (paclitaxel), or 7-hydroxystaurosporine (UCN-01). Over a 2-4 day treatment period with GCV or the other four drugs, protein levels of the apoptosis agonist Bak increased 1.5-to 3-fold, whereas a corresponding decrease in the levels of the apoptosis antagonist, Bcl-X L , was observed in butyrate-, CPT-, and 7-hydroxystaurosporine (UCN-01)-treated cells. GCV and paclitaxel treatments resulted in increased levels of Bcl-X L . In two-drug combinations with GCV plus one of the four other drugs, increased tumor cell killing was found with GCV plus UCN-01 or with some GCV/butyrate combinations; the other two tested combinations were largely antagonistic. The GCV/UCN-01 and GCV/butyrate combinations resulted in increased Bak and decreased Bcl-X L protein levels, while the GCV/CPT and GCV/paclitaxel combinations resulted in increased levels of both proteins. The results highlight the potential for new combination therapies of HSV-TK/GCV and chemotherapeutic drugs that result in increased tumor cell apoptosis for future treatments of colon cancer.

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Section: Discussionsupporting

confidence: 77%

Two-drug combinations that increase apoptosis and modulate Bak and Bcl-XL expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase

et al. 2000

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“…Whether the enhanced radioresponse during combined use of paclitaxel and radiation is the consequence of cell accumulation in the radiosensitive G 2 /M phase of the cell cycle has not been clarified. It has been suggested that the mitotic block is a critical determinant of paclitaxel-induced cell death, 43 but Milross et al 44 found the antitumor effect of paclitaxel to correlate with paclitaxelinduced and baseline apoptosis, not with mitotic arrest, although mitotic arrest was apparent in all tumor types they reported, to varying degrees. In the current study 5 cell lines were also tested with flow cytometry after 24 and 48 hr of exposure to paclitaxel.…”

Section: Discussionmentioning

confidence: 98%

Paclitaxel combined with fractionated radiation in vitro: A study with vulvar squamous cell carcinoma cell lines

Raitanen

Rantanen

Kulmala

et al. 2001

Intl Journal of Cancer

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Concurrent paclitaxel and radiation has given promising results in the treatment of a variety of solid tumors. We wanted to test the efficacy of this combination for vulvar carcinoma, which currently has a poor outcome in advanced stages. The radiation sensitivity, sublethal damage repair (SLDR) capacity and effect of paclitaxel during fractionated radiation were assessed in our study on 7 vulvar inherently radioresistant squamous cell carcinoma (SCC) cell lines. The 96-well plate clonogenic assay was used. Survival data were fitted to the linear quadratic model. The area under the curve (AUC), equivalent to mean inactivation dose (D ), was obtained with numerical integration. AUC ratios between single-dose radiation and fractionated radiation with or without paclitaxel were used to determine the SLDR of the cell lines and the effect of paclitaxel on it. Seven currently tested vulvar SCC cell lines were found to have a limited capacity of repairing sublethal damage (SLD). Only 3 of them presented SLDR of significance. The effect of concurrent radiation and paclitaxel was clearly additive when the radiation dose was fractionated in most of the cell lines. In addition, 2 of the cell lines having SLDR exhibited a trend toward losing the repair capacity when paclitaxel was present during the irradiation. In addition, the survival curve of the UM-SCV-1A cell line gave the impression of a true paclitaxel effect on SLDR. Paclitaxel used concurrently with fractionated radiation showed effectiveness on vulvar carcinoma. The effect was at least additive and could even be expected to abrogate the SLDR during split-dose radiation.

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“…It constitutes a systematic means of cell suicide during normal embryonic development and morphogenesis (von Wangenheim and Peterson, 1998), aging (Monti et al, 1992) or in response to pathogenic infections and other irreparable cell damage. Induction of apoptosis by anticancer drugs has been demonstrated using, for example, paclitaxel (Milross et al, 1996) or cisplatin (Trimmer and Essigmann, 1999). Recently, after cell treatment with ionising radiation, a 'premitotic' and a 'postmitotic' apoptosis could be distinguished as a function of the morphological features of the treated cells (Shinomiya et al, 2000).…”

mentioning

confidence: 99%

In vivo evolution of tumour cells after the generation of double-strand DNA breaks

et al. 2003

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In vitro, the ratio of single-to double-strand DNA breaks (DSB) and their absolute values determine the cell death pathway. The consequences of the generation of various numbers of DSB generated in vivo in tumour cells have been analysed in two different experimental tumour models. Synchronisation of DSB generation and control of their number have been achieved using different doses of bleomycin (BLM) and tumour cell permeabilisation by means of locally delivered electric pulses. According to BLM dose, different cell death pathways are observed. At a low therapeutic dose, a mitotic cell death pathway is detected. It is characterised by the appearance of 'atypical mitosis', TUNEL and caspase-3 positive, 24 h after the treatment, and later by the presence of typical apoptotic figures, mainly TUNEL positive but caspase-3 negative. Caspase-3 is thus an early marker of apoptosis. Mitotic cell death is also followed by lymphocytic infiltration reaction. At high doses of BLM, pseudoapoptosis is detected within a few minutes after the treatment. These cell death pathways are discussed as a function of the number of DSB generated, by comparison with previous results obtained in vitro using BLM or ionising radiation.

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Relationship of Mitotic Arrest and Apoptosis to Antitumor Effect of Paclitaxel

Cited by 253 publications

References 30 publications

Two-drug combinations that increase apoptosis and modulate Bak and Bcl-XL expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase

Two-drug combinations that increase apoptosis and modulate Bak and Bcl-XL expression in human colon tumor cell lines transduced with herpes simplex virus thymidine kinase

Paclitaxel combined with fractionated radiation in vitro: A study with vulvar squamous cell carcinoma cell lines

In vivo evolution of tumour cells after the generation of double-strand DNA breaks

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