Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer

Yingming Li, Bahaa S. Malaeb, Zhong Ze Li, Melissa G. Thompson, Zhi Chen, David R. Corey, Jer Tsong Hsieh, Jerry W. Shay, Kenneth S. Koeneman

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Abstract

BACKGROUND. Recurrent prostate cancer can be osseous, androgen independent and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer. METHODS. C4-2B was pre-treated with a match or mismatch TEI for 6 weeks and then inoculated into nude mice subcutaneously or intraosseously. In a separate experiment, untreated C4-2B was injected into femur of nude mice. The mice were divided into seven systemic "combination" treatment groups of control, Ad-BSP-E1a virus, docetaxel, mismatch and match TEI. Serum PSA was followed longitudinally. Histology analyses and histomorphometry were performed. Repeated measure analysis was applied for statistical analysis and Bonferroni method was used in multiple comparisons. RESULTS. In the pre-treated study, the PSA of match treated cells in subcutaneous or intraosseous model was significantly lower than mismatch TEI or PBS treated group (P < 0.05). Histology revealed increased fibrosis, apoptosis and decreased PSA staining in the match TEI treated subcutaneous xenografts. In the combination treatment study, the PSA was significantly lower in single/double treatment and triple treatment than control (P < 0.05). Histology revealed that triple therapy mice had normal femur architecture. Histomorphometrics revealed that the area of femur tumor and woven bone was significantly positively correlated (P = 0.007). CONCLUSIONS. Multiple lines of data point toward the efficacy of systemically administered telomerase inhibitors. Combining cytotoxic regimens with telomerase inhibitors could be beneficial in controlling prostate cancer. Clinical trials are warranted to explore the efficacy of TEI in prostate cancer.

Original languageEnglish (US)
Pages (from-to)616-629
Number of pages14
JournalProstate
Volume70
Issue number6
DOIs
StatePublished - May 1 2010

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Keywords

  • Adenoviral vectors
  • Bone metastasis
  • Combination therapy
  • Hormone refractory prostate cancer
  • Oligonucleotides
  • Small molecule telomerase inhibitors

Cite this

Li, Y., Malaeb, B. S., Li, Z. Z., Thompson, M. G., Chen, Z., Corey, D. R., Hsieh, J. T., Shay, J. W., & Koeneman, K. S. (2010). Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer. Prostate, 70(6), 616-629. https://doi.org/10.1002/pros.21096