Perioperative Co-Administration of Polyphenon E and Siliphos Inhibited Subcutaneous and Hepatic Tumor Growth Yet Did Not Impair Wound Healing in the Murine Setting

Xiaohong Yan, PhD, Aqeel Ahmed, MD, Thomas Gardner, MCE, Michael Grieco, MD, Sonali A Herath, BS, Abu Nasar, MS, Daniel Kirchoff, MD, Joonho Jang, MD, HMC Shantha Kumara, PhD, Carlos Cordon-Cardo, MD, Richard L Whelan, MD. Sr Luke Roosevelt Hospital Center,Department of Colon and Rectal Surgery,New York,NY 10019,USA

Introduction: Surgical trauma is associated with immunosuppression and proangiogenic plasma protein changes that may promote the growth of residual tumor after surgery. Perioperative (periop) anti-cancer drug treatment is logical, however, standard chemotherapy is not used because of wound and anastomotic healing concerns. Polyphenon E (PolyE) from green tea and Siliphos (Silip) from the milk thistle plant have individually been shown to inhibit tumor growth in vivo. We hypothesized that administration of both drugs would inhibit periop tumor growth and development without impairing wound healing. Methods: Separate subcutaneous and hepatic tumor studies were done as well as a wound healing study in Balb/c mice. For all studies PolyE was given via the drinking water (0.5% concentration) and Silip (200mg/Kg) via oral gavage on a daily basis. Subcutaneous Tumor Model: Subcut injections of 5X10⁴ CT26 cells were given to control and PolyE/Silip group mice (n=45 each) and treatment started a day later. On Day10 each group was further randomized into 3 groups (n=15) that underwent: 1) anesthesia alone, 2) CO2 pneumo, or 3) sham midline laparotomy. Drugs were continued in the treatment group until Day 24 (POD14) when all tumors were excised and weighed. Hepatic Mets Model: 60 mice were divided into 4 groups (n=15) that received the following daily: 1) placebo, 2) PolyE, 3) Silip, 4) Poly E + Silip. After 7 days of treatment all mice underwent laparotomy and portal vein injection of 1×104 CT26 cells. Daily treatment was continued until POD19 when the mice were sacrificed, livers excised and surface tumors counted. Wound Healing Study: 60 mice were divided into 4 groups (n=15) that received daily: 1) placebo, 2) PolyE, 3) Silip, 4) Poly E + Silip. On Day 7 all mice underwent a midline laparotomy and gastrotomy that were suture closed. On POD7, the mice were sacrificed and the abdominal wounds excised and assessed via tensometry and collagen content analysis. The stomachs were also excised and the bursting pressures determined. Results: Subcutaneous Model: When compared to control group median tumor weight (0.21g), the PolyE/Silip group tumors (0.04g) were significantly smaller (p=0.006). Hepatic Mets Model: PolyE and Silip alone did not significantly impact the surface liver tumor count. The PolyE/Silip combination, however, resulted in fewer mets (2.4±1.8) vs the control group (5.4±4.3; p=0.024). Wound Healing Study: PolyE and Silip, alone, did not alter any wound healing parameter. Also, there was no significant difference between the Control and the combined PolyE/Silip groups in regards to median collagen content (22.5±6.5ug/mg vs. 22.1±10.8ug/mg; p=0.589) or breaking strength of the abdominal wall wounds (0.91X10^-3 J, IQR 0.49-2.53X10^-3 J vs. 1.43X10^-3 J, IQR 0.81-2.35X10^-3 J; p=0.381). Similarly, there was no significant difference in the mean gastric bursting pressure between control (98.2±36.0mmHg) and PolyE/Silip (84.5±9.8mmHg) groups. Conclusions: Periop PolyE/Silip inhibited the growth of subcutaneous and hepatic tumors yet did not significantly impair abdominal wall or gastric wound healing. A Phase 1 study wherein these drugs are given to cancer patients immediately before and after surgery may be warranted.