Icodextrin enhances survival in an intraperitoneal ovarian cancer murine model utilizing gene therapy.
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 (Delta24-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+Delta24-RGD, or icodextrin+Delta24-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+Delta24-RGD group, and 105 days for icodextrin+Delta24-RGD (p=0.023). Of note, 5 of the 10 mice in the icodextrin+Delta24-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.
Rocconi
Rodney P
RP
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 618 20th Street South, Old Hillman Building-Room 538, Birmingham, AL 35249-7333, USA. rocconi@uab.edu
Numnum
Michael T
MT
Zhu
Zeng B
ZB
Lu
Baogen
B
Wang
Minghui
M
Rivera
Angel A
AA
Stoff-Khalili
Mariam
M
Alvarez
Ronald D
RD
Curiel
David T
DT
Makhija
Sharmila
S
D000818:Animals; D015314:Dialysis Solutions / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005936:Glucans / Q000008:administration & dosage / Q000627:therapeutic use*; D005947:Glucose / Q000008:administration & dosage / Q000627:therapeutic use*; D000077607:Icodextrin; D007263:Infusions, Parenteral; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*
D015314:Dialysis Solutions; D005936:Glucans; D000077607:Icodextrin; D005947:Glucose