Towards fibroid gene therapy: Adenovirus-mediated delivery of herpes simplex virus 1 thymidine kinase gene/ganciclovir shrinks uterine leiomyoma in the Eker rat model

Memy Hassan, Dong Zhang, Salama Salama, Farid Hamada, Hossam Arafa, Hala Fouad, Cheryl Walker, Ayman Al-Hendy

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background/Aims: The objective of this study was to assess in vivo gene therapy of uterine leiomyomas in the Eker rat model using adenovirus (Ad)-mediated delivery of herpes simplex virus 1 thymidine kinase gene (HSV1TK) followed by ganciclovir (GCV) treatment. Methods: We randomized 27 female Eker rats with MRI-confirmed uterine leiomyomas to a single treatment with direct intra-tumor injection of Ad-HSV1TK/GCV, Ad-LacZ/GCV, or medium alone. Samples were collected from tumors, other body organs, and blood at 10, 20, and 30 days after treatment to assess the safety and efficacy of the treatment. Results: Ad-HSV1TK/GCV treatment significantly decreased uterine fibroid volume by 75 ± 16, 58.7 ± 6.3, and 67.5 ± 27.5%, of the pretreatment volume at days 10, 20, and 30, respectively. Ad-HSV1TK/GCV increased caspase-3 activity, Bax expression, and TUNEL apoptosis marker, and it decreased cyclin D1, PCNA, Bcl2, and PARP protein expressions. Ad transfection induced local CD4+ and CD8+ infiltration and serum anti-Ad antibodies. Additionally, Ad transfection was tumor-localized and safe to non-target tissues. Conclusion: These studies demonstrate a marked efficiency and high safety for the Ad-HSV1TK/GCV therapeutic approach in the context of Eker rat uterine leiomyomas and provide essential preclinical data for the development of Ad-HSV1TK/GCV gene therapy for uterine fibroids.

Original languageEnglish (US)
Pages (from-to)19-32
Number of pages14
JournalGynecologic and Obstetric Investigation
Volume68
Issue number1
DOIs
StatePublished - Jul 1 2009

Fingerprint

Ganciclovir
Thymidine Kinase
Human Herpesvirus 1
Leiomyoma
Adenoviridae
Genetic Therapy
Genes
Transfection
Therapeutics
Safety
Neoplasms
Cyclin D1
In Situ Nick-End Labeling
Proliferating Cell Nuclear Antigen
Caspase 3
Anti-Idiotypic Antibodies
Apoptosis
Injections

Keywords

  • Eker rat
  • Gene therapy
  • HSV1TK/GCV
  • Leiomyoma

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Towards fibroid gene therapy : Adenovirus-mediated delivery of herpes simplex virus 1 thymidine kinase gene/ganciclovir shrinks uterine leiomyoma in the Eker rat model. / Hassan, Memy; Zhang, Dong; Salama, Salama; Hamada, Farid; Arafa, Hossam; Fouad, Hala; Walker, Cheryl; Al-Hendy, Ayman.

In: Gynecologic and Obstetric Investigation, Vol. 68, No. 1, 01.07.2009, p. 19-32.

Research output: Contribution to journalArticle

Hassan, Memy ; Zhang, Dong ; Salama, Salama ; Hamada, Farid ; Arafa, Hossam ; Fouad, Hala ; Walker, Cheryl ; Al-Hendy, Ayman. / Towards fibroid gene therapy : Adenovirus-mediated delivery of herpes simplex virus 1 thymidine kinase gene/ganciclovir shrinks uterine leiomyoma in the Eker rat model. In: Gynecologic and Obstetric Investigation. 2009 ; Vol. 68, No. 1. pp. 19-32.
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abstract = "Background/Aims: The objective of this study was to assess in vivo gene therapy of uterine leiomyomas in the Eker rat model using adenovirus (Ad)-mediated delivery of herpes simplex virus 1 thymidine kinase gene (HSV1TK) followed by ganciclovir (GCV) treatment. Methods: We randomized 27 female Eker rats with MRI-confirmed uterine leiomyomas to a single treatment with direct intra-tumor injection of Ad-HSV1TK/GCV, Ad-LacZ/GCV, or medium alone. Samples were collected from tumors, other body organs, and blood at 10, 20, and 30 days after treatment to assess the safety and efficacy of the treatment. Results: Ad-HSV1TK/GCV treatment significantly decreased uterine fibroid volume by 75 ± 16, 58.7 ± 6.3, and 67.5 ± 27.5{\%}, of the pretreatment volume at days 10, 20, and 30, respectively. Ad-HSV1TK/GCV increased caspase-3 activity, Bax expression, and TUNEL apoptosis marker, and it decreased cyclin D1, PCNA, Bcl2, and PARP protein expressions. Ad transfection induced local CD4+ and CD8+ infiltration and serum anti-Ad antibodies. Additionally, Ad transfection was tumor-localized and safe to non-target tissues. Conclusion: These studies demonstrate a marked efficiency and high safety for the Ad-HSV1TK/GCV therapeutic approach in the context of Eker rat uterine leiomyomas and provide essential preclinical data for the development of Ad-HSV1TK/GCV gene therapy for uterine fibroids.",
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AU - Salama, Salama

AU - Hamada, Farid

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AU - Walker, Cheryl

AU - Al-Hendy, Ayman

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