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Increase of BCNU sensitivity by wt-p53 gene therapy in glioblastoma lines depends on the administration schedule

Gene Therapy volume 6, pages 1064–1072 (1999)Cite this article

Abstract

In this article, we investigated the effect induced by the reintroduction of wild-type p53 (wt-p53) protein on BCNU sensitivity in the ADF glioblastoma line. Using a wt-p53 recombinant adenovirus (Ad-p53), we demonstrated that exogenous wt-p53 expression was able to increase the sensitivity to BCNU in ADF cells. Interestingly, this effect was more evident when Ad-p53 infection was performed after BCNU treatment compared with the opposite sequence. To understand the biological basis of these different behaviors, we analyzed the cell cycle of the differently treated cells. We found that Ad-p53 infection induced a persistent accumulation of cells in the G0/G1 phase while, as expected, BCNU induced a block in the G2-M phase. Ad-p53→BCNU sequence did not significantly mod- ify the cell cycle profile in respect of Ad-p53 infected cells. In contrast, BCNU→Ad-p53 sequence provoked G2-M arrest similar to that observed after treatment with BCNU alone, but prevented the later recovery of the cells through the cell cycle, by driving the cells to apoptotic death. These results demonstrate that the administration sequence is important to increase drug sensitivity. To generalize the phenomenon observed on ADF line, the antiproliferative effect of the two different schedules was analyzed on other glioblastoma lines (A172, CRS-A2, U373MG) with different BCNU sensitivity and p53 status. The data obtained confirm that the wt-p53 gene transfer enhances BCNU sensitivity in glioblastoma cells depending on the administration sequence.

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Acknowledgements

We thank S Bacchetti and F Graham for generous gift of recombinant adenovirus and B Vogelstein for providing the PG13-CAT and MG15-CAT vectors. We are grateful to Mrs Simona Righi for typing this manuscript. AB is a recipient of fellowships from AIRC. AR is a recipient of fellowships from FIRC. This work was supported by Italian Association for Cancer Research, Ministero della Sanità and Italy-USA Program.

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Authors and Affiliations

  1. Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Rome, Italy

    A Biroccio, D Del Bufalo, A Ricca, C D’Angelo & G Zupi

  2. Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, Italy

    G D’Orazi, A Sacchi & S Soddu

  3. Department of Oncology and Neurosciences, University G D’Annunzio, Chieti, Italy

    G D’Orazi

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  1. A Biroccio
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Biroccio, A., Del Bufalo, D., Ricca, A. et al. Increase of BCNU sensitivity by wt-p53 gene therapy in glioblastoma lines depends on the administration schedule. Gene Ther 6, 1064–1072 (1999). https://doi.org/10.1038/sj.gt.3300935

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