Icodextrin enhances survival in an intraperitoneal ovarian cancer murine model utilizing gene therapy

Rodney P. Rocconi, Michael T. Numnum, Zeng B. Zhu, Baogen Lu, Minghui Wang, Angel A. Rivera, Mariam Stoff-Khalili, Ronald D. Alvarez, David T. Curiel, Sharmila K. Makhija

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Objective.: Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods.: Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20%) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS + Δ24-RGD, or icodextrin + Δ24-RGD. Survival data were plotted on Kaplan-Meier curve and statistical calculations performed using the log-rank test. Results.: There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS + Δ24-RGD group, and 105 days for icodextrin + Δ24-RGD (p = 0.023). Of note, 5 of the 10 mice in the icodextrin + Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions.: These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development.

Original languageEnglish (US)
Pages (from-to)985-989
Number of pages5
JournalGynecologic Oncology
Volume103
Issue number3
DOIs
StatePublished - Dec 2006
Externally publishedYes

Fingerprint

Genetic Therapy
Ovarian Neoplasms
Survival
Adenoviridae
icodextrin
Cell Line
Glucans
Dialysis Solutions
Peritoneal Dialysis
Therapeutic Uses
Neoplasms
Animal Models
Viruses
Polymerase Chain Reaction

Keywords

  • Gene therapy
  • Icodextrin
  • Intraperitoneal
  • Ovarian cancer

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Icodextrin enhances survival in an intraperitoneal ovarian cancer murine model utilizing gene therapy. / Rocconi, Rodney P.; Numnum, Michael T.; Zhu, Zeng B.; Lu, Baogen; Wang, Minghui; Rivera, Angel A.; Stoff-Khalili, Mariam; Alvarez, Ronald D.; Curiel, David T.; Makhija, Sharmila K.

In: Gynecologic Oncology, Vol. 103, No. 3, 12.2006, p. 985-989.

Research output: Contribution to journalArticle

Rocconi, RP, Numnum, MT, Zhu, ZB, Lu, B, Wang, M, Rivera, AA, Stoff-Khalili, M, Alvarez, RD, Curiel, DT & Makhija, SK 2006, 'Icodextrin enhances survival in an intraperitoneal ovarian cancer murine model utilizing gene therapy', Gynecologic Oncology, vol. 103, no. 3, pp. 985-989. https://doi.org/10.1016/j.ygyno.2006.06.005
Rocconi, Rodney P. ; Numnum, Michael T. ; Zhu, Zeng B. ; Lu, Baogen ; Wang, Minghui ; Rivera, Angel A. ; Stoff-Khalili, Mariam ; Alvarez, Ronald D. ; Curiel, David T. ; Makhija, Sharmila K. / Icodextrin enhances survival in an intraperitoneal ovarian cancer murine model utilizing gene therapy. In: Gynecologic Oncology. 2006 ; Vol. 103, No. 3. pp. 985-989.
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abstract = "Objective.: Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods.: Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20{\%}) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS + Δ24-RGD, or icodextrin + Δ24-RGD. Survival data were plotted on Kaplan-Meier curve and statistical calculations performed using the log-rank test. Results.: There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS + Δ24-RGD group, and 105 days for icodextrin + Δ24-RGD (p = 0.023). Of note, 5 of the 10 mice in the icodextrin + Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions.: These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development.",
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AU - Numnum, Michael T.

AU - Zhu, Zeng B.

AU - Lu, Baogen

AU - Wang, Minghui

AU - Rivera, Angel A.

AU - Stoff-Khalili, Mariam

AU - Alvarez, Ronald D.

AU - Curiel, David T.

AU - Makhija, Sharmila K.

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N2 - Objective.: Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods.: Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20%) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS + Δ24-RGD, or icodextrin + Δ24-RGD. Survival data were plotted on Kaplan-Meier curve and statistical calculations performed using the log-rank test. Results.: There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS + Δ24-RGD group, and 105 days for icodextrin + Δ24-RGD (p = 0.023). Of note, 5 of the 10 mice in the icodextrin + Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions.: These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development.

AB - Objective.: Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods.: Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20%) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS + Δ24-RGD, or icodextrin + Δ24-RGD. Survival data were plotted on Kaplan-Meier curve and statistical calculations performed using the log-rank test. Results.: There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS + Δ24-RGD group, and 105 days for icodextrin + Δ24-RGD (p = 0.023). Of note, 5 of the 10 mice in the icodextrin + Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions.: These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development.

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