2002
DOI: 10.1038/sj.onc.1205280
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Ganciclovir-induced apoptosis in HSV-1 thymidine kinase expressing cells: critical role of DNA breaks, Bcl-2 decline and caspase-9 activation

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Cited by 106 publications
(114 citation statements)
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“…Increased Bax and decreased Bcl-xL levels after GCV treatment support the higher sensitivity to GCV of LM05e/tk and B16/tk monolayers with respect to their respective spheroids, where GCV increased both Bax and Bcl-xL (3D-LM05e) or did not modify them (3D-B16). 4,32,33 In the case of LM3, a similar GCV-induced Bax increase, without changes in Bcl-xL levels, could explain the similar GCV sensitivity and the bystander effect of 2D-and 3D-LM3 cultures. 4,32,33 Additional factor(s) should be involved in the bystander effect of nonreplicating spheroid cells Although considerably high transgene expression by itself could account for the efficacy of the HSVtk/GCV suicide system in LM3 spheroids, the situation was different for the other cell lines tested.…”
Section: Spheroids Displayed Enhanced Transgene Expressionmentioning
confidence: 94%
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“…Increased Bax and decreased Bcl-xL levels after GCV treatment support the higher sensitivity to GCV of LM05e/tk and B16/tk monolayers with respect to their respective spheroids, where GCV increased both Bax and Bcl-xL (3D-LM05e) or did not modify them (3D-B16). 4,32,33 In the case of LM3, a similar GCV-induced Bax increase, without changes in Bcl-xL levels, could explain the similar GCV sensitivity and the bystander effect of 2D-and 3D-LM3 cultures. 4,32,33 Additional factor(s) should be involved in the bystander effect of nonreplicating spheroid cells Although considerably high transgene expression by itself could account for the efficacy of the HSVtk/GCV suicide system in LM3 spheroids, the situation was different for the other cell lines tested.…”
Section: Spheroids Displayed Enhanced Transgene Expressionmentioning
confidence: 94%
“…4,32,33 In the case of LM3, a similar GCV-induced Bax increase, without changes in Bcl-xL levels, could explain the similar GCV sensitivity and the bystander effect of 2D-and 3D-LM3 cultures. 4,32,33 Additional factor(s) should be involved in the bystander effect of nonreplicating spheroid cells Although considerably high transgene expression by itself could account for the efficacy of the HSVtk/GCV suicide system in LM3 spheroids, the situation was different for the other cell lines tested. When seeded at high density, increasing cell-to-cell contacts, LM05e and B16 monolayers diminished their growth rates, GCV sensitivity and bystander effect, behaving as slow growing LM05e spheroids (Figs 1-3).…”
Section: Spheroids Displayed Enhanced Transgene Expressionmentioning
confidence: 94%
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“…Previously, it has been reported that GCV-TP is incorporated into cellular DNA, cells complete one round of mitosis, arrest in S-phase of the cell-cycle resulting in doublestranded breaks, and ultimately go into apoptosis [15,34]. The appearance of apoptotic cells at 24 h, which increased greatly at 36-72 h has been reported following the incubation of a CHO cellline stably expressing HSV1-TK with GCV [15]. Our findings are in line with this apoptotic time-scale, as we observed in the case of both EHV4 TK WT-GFP and EHV4 TK S144H-GFP that at GCV concentrations in excess of the EC 50 value, cell-death occurs from 24 h onwards (Fig.…”
Section: Discussionmentioning
confidence: 99%
“…The GCV-TP metabolite has been implicated in the initiation of the apoptosis pathway, though the exact mechanism whereby the cell becomes apoptotic is still unknown. Briefly, GCV-TP is incorporated in the elongating DNA chain resulting in S-phase cell-cycle arrest, and/or GCV-TP competitively inhibits the cellular DNA polymerases, resulting in inhibition of DNA synthesis, and ultimately apoptosis [9][10][11][12][13][14][15].…”
Section: Introductionmentioning
confidence: 99%