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Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer

Cancer Gene Therapy volume 10, pages 224–238 (2003)Cite this article

Abstract

A cohort study was designed to evaluate the efficiency of gene transfer and whether biological activity from the expressed therapeutic gene resulted after administration of a recombinant adenovirus containing the human wild-type p53 (p53wt) gene (rAd-p53 SCH 58500). The cohort study was conducted in five trial subjects with recurrent ovarian cancer. Each trial subject received multiple cycles of rAd-p53 SCH 58500, each cycle comprised of doses of 7.5 × 1013 particles on each of five consecutive days. Subjects were treated with rAd-p53 SCH 58500 alone during Cycle 1 and in combination with gemcitabine during the subsequent cycles. Both tumor biopsies and peritoneal aspirates were collected and evaluated for gene transfer and evidence of the biological activities of the expressed p53wt gene. Using quantitative PCR and RT-PCR, and in situ PCR, gene transfer and expression were documented in tumor biopsies (four of five patients) collected from Cycle 1. Furthermore, upregulation of p21/WAF1, bax and mdm-2, and downregulation of survivin were observed in these same tumor biopsy samples, suggesting that intraperitoneal administration of rAd-p53 SCH 58500 leads to detectable p53 biological activity in target tumor tissue. In addition, gene transfer and its expression were observed in cells obtained from peritoneal aspirates. These fluids were mainly comprised of polymorphonuclear neutrophils, indicating that successful gene transfer can be achieved by multiple cycle intraperitoneal administration of recombinant adenovirus.

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Acknowledgements

We thank the patients and their families for their participation in this bioanalytical cohort of the trial. We thank Michelle Kerin and Melanie Hattermann for the tremendous effort they put in coordinating study samples. We would also like to thank Dr. Suxing Liu for her helpful discussion of the survivin data.

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Authors and Affiliations

  1. Canji, Inc., San Diego, California, USA

    Shu Fen Wen, Erlinda Quijano, Jeremy Shinoda, Dan Maneval & Beth Hutchins

  2. The University of Iowa Hospital and Clinic, Iowa City, Iowa, USA

    Vikas Mahavni & Richard Buller

  3. Schering-Plough Research Institute, Kenilworth and Union, New Jersey, USA

    Michael Grace, Mary Lynn Musco-Hobkinson, Tong-Yuan Yang, Yuetian Chen & JoAnn Horowitz

  4. Universitäts-Frauenklinik, Freiburg, Germany

    Ingo Runnenbaum

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  1. Shu Fen Wen
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Correspondence to Shu Fen Wen.

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Wen, S., Mahavni, V., Quijano, E. et al. Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer. Cancer Gene Ther 10, 224–238 (2003). https://doi.org/10.1038/sj.cgt.7700562

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  • DOI: https://doi.org/10.1038/sj.cgt.7700562

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