Abstract
BackgroundThis study aimed to measure the toxicity resulting from collagenase administration to the peritoneal cavity in a pig model as a preliminary step to break down the stroma surrounding tumors.MethodsEight pigs were treated with 2 different collagenase concentrations previously tested in rats by our group. Time and temperature were controlled using a peritoneal lavage system (PRS System, Combat Medical Ltd.) identical to that used in human surgeries through hyperthermic intraperitoneal chemotherapy (HIPEC); 2 additional pigs were treated with peritoneal lavage only. Samples of blood and peritoneal fluid were collected pre-treatment, immediately after treatment, and 24 h postoperatively. In addition, histological studies and blood collagenase levels were measured.ResultsNo complications were observed during the surgeries. Intraoperative images evidenced the release of peritoneal tissue during collagenase treatment. After surgery, the animals showed no signs of pain. Diet and mobility were normal at 4 h postoperatively, and there were no significant differences in hematologic or biochemical parameters. Quantification of MMP1 and MMP2 in all samples as measured by absorbance showed no differences in blood collagenase levels between pre-treatment, post-treatment, and 24 h postoperatively.None of the animals treated with collagenase showed peritoneal adhesions during the second surgery. Histologically, peritoneal organs and serous structures did not show any microscopic alterations associated with collagenase treatment in any group.ConclusionLavage of the peritoneal cavity with doses of up to 100,000 collagen digestion units/animal for 30 min is safe and removes connective tissue from the peritoneal cavity.
Highlights
This study aimed to measure the toxicity resulting from collagenase administration to the peritoneal cavity in a pig model as a preliminary step to break down the stroma surrounding tumors
Solid tumors are surrounded by tumor stroma that is resistant to most drugs
In group 1, 6 animals underwent lavage of the peritoneal cavity at 50,000 collagen digestion units (CDU) or 369.2 g of collagenase (GIDZyme-2 GMP, Spain) in 1.5 L of peritoneal dialysis solution; in group 2, 2 animals underwent lavage of the peritoneal cavity at 100,000 CDUs or 738.4 g of collagenase in 1.5 L of peritoneal dialysis solution, and in Group 3, lavage was performed in 2 animals with 1.5 L of the same solution
Summary
This study aimed to measure the toxicity resulting from collagenase administration to the peritoneal cavity in a pig model as a preliminary step to break down the stroma surrounding tumors. Solid tumors are surrounded by tumor stroma that is resistant to most drugs This microenvironment protects the tumor and complicates nonsurgical approaches, Garcia‐Arranz et al World Journal of Surgical Oncology (2022) 20:53 which limits the ability of therapeutic agents to target cancer cells [1]. Disrupting this extracellular matrix, which is composed mainly of collagen, could facilitate the penetration of drugs into tumors and improve the therapeutic response [2,3,4]. An approach using a system to apply collagenase in a rat tumor model has shown that proper control of enzyme time and concentration is essential [7]
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