Cancer gene therapy using a survivin mutant adenovirus

J Clin Invest. 2001 Oct;108(7):981-90. doi: 10.1172/JCI12983.


We have constructed a replication-deficient adenovirus encoding a nonphosphorylatable Thr(34)-->Ala mutant of the apoptosis inhibitor survivin (pAd-T34A) to target tumor cell viability in vitro and in vivo. Infection with pAd-T34A caused spontaneous apoptosis in cell lines of breast, cervical, prostate, lung, and colorectal cancer. In contrast, pAd-T34A did not affect cell viability of proliferating normal human cells, including fibroblasts, endothelium, or smooth muscle cells. Infection of tumor cells with pAd-T34A resulted in cytochrome c release from mitochondria, cleavage of approximately 46-kDa upstream caspase-9, processing of caspase-3 to the active subunits of approximately 17 and 19 kDa, and increased caspase-3 catalytic activity. When compared with chemotherapeutic regimens, pAd-T34A was as effective as taxol and considerably more effective than adriamycin in induction of tumor cell apoptosis and enhanced taxol-induced cell death. In three xenograft breast cancer models in immunodeficient mice, pAd-T34A suppressed de novo tumor formation, inhibited by approximately 40% the growth of established tumors, and reduced intraperitoneal tumor dissemination. Tumors injected with pAd-T34A exhibited loss of proliferating cells and massive apoptosis by in situ internucleosomal DNA fragmentation. These data suggest that adenoviral targeting of the survivin pathway may provide a novel approach for selective cancer gene therapy.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviruses, Human
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Apoptosis
  • Cell Cycle
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / physiology*
  • Chromosomal Proteins, Non-Histone / therapeutic use
  • Cysteine Proteinase Inhibitors*
  • Doxorubicin / pharmacology
  • Gene Expression
  • Genetic Therapy / methods
  • Genetic Vectors
  • HeLa Cells
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, SCID
  • Microtubule-Associated Proteins*
  • Mutagenesis, Site-Directed
  • Neoplasm Proteins
  • Neoplasms / therapy*
  • Neoplasms, Experimental
  • Paclitaxel / pharmacology
  • Survivin
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • BIRC5 protein, human
  • Chromosomal Proteins, Non-Histone
  • Cysteine Proteinase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Survivin
  • Doxorubicin
  • Paclitaxel