Intraperitoneal collagenase as a novel therapeutic approach in an experimental model of colorectal peritoneal carcinomatosis

Abstract

The usefulness of local collagenase in therapeutic approaches to solid tumors has been tested recently. In this study, we evaluate the safety and efficacy of intraperitoneal collagenase associated or not to mitomycin for treatment of colorectal peritoneal metastases in an experimental rat model. Using a fixed-dose procedure, we found that a dose of collagenase of 37 IU/mL administered for 15 min with a hyperthermia pump at 37.5 °C, both in isolation or associated to sequential treatment with intraperitoneal mitomycin, led to a macroscopic decrease in tumor volume as evaluated by the modified peritoneal cancer index (mPCI). Concerning the safety of the procedure, the animals showed no physiological or behavioral disorders during 8 weeks of follow-up. Local treatment for peritoneal metastases of colorectal origin with intraperitoneal collagenase has proved safe and effective in an experimental murine model. Therefore, the stroma-first approach by enzymatic breakdown of collagen from the tumor's extracellular matrix provides a new therapeutic target for colorectal peritoneal metastases.

Toxicity Study in a Pig Model of Intraperitoneal Collagenase as an "Enzymatic Scalpel" Directed to Breaks Stroma in Order to Generate a New Perspective for Peritoneal Carcinomatosis Approach. An Experimental Research.

“…We had demostrated that lavage the peritoneal cavity for 30 minutes with 50000 or 100000CDU of collagenase diluted in 1.5L of saline solution between 36-38ºC is safe and does not generate any sign of toxicity in the treated animals. This conclusion allows us, together with the e cacy data previously obtained in a rat model [5], to propose to the health authorities the use of collagenase lavage of the peritoneal cavity in a clinical trial for the conditioning or treatment of solid peritoneal tumors.…”

“…An important point is the activity time of collagenase, in previous studies, same articles had demonstrated that at 30 minutes collagenase activity is residual using in peritoneal cavity of mice [5,13]; in our assay and considering the high concentration of collagen existing in the peritoneal cavity, we are sure that in 30 minutes the catalytic activity of the enzyme has been "exhausted".…”

“…Solid tumors are surrounded by a stroma resistant to most drugs that makes their nonsurgical approach di cult, this microenvironment protect to tumor against therapeutic agents to target cancer cells` [1].Breaking this extracellular matrix (composed mainly of collagen) could facilitate the penetration of drugs into tumors and improve the therapeutic tumor response [2][3][4] .Previous work by our group on rats has shown that the use of intraperitoneal collagenase, controlling the time and concentration, degrades the tumor stroma without causing damage to the organs and tissues of the animals [5].In order to obtain authorization from regulatory agencies, we decided to conduct a toxicity study of the application of collagenase at the peritoneal level on a large animal model. Degradation of the extracellular matrix using intravenous collagenase has been shown to increase drug penetration in murine tumors [6].…”

Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer

“…Intra-tumoral or intravenous injection of collagenase increased the diffusion of large drug molecules in tumor models (54). Intraperitoneal administration of collagenase was reported to increase the e cacy of chemotherapy by cleaving the tumor stroma in a rat model of colorectal cancer peritoneal metastasis (55). Ocriplasmin is used to remove adhesions in symptomatic vitreomacular adhesion (51).…”

The Role of CAR-T Cells in Peritoneal Carcinomatosis from Gastric Cancer: Rationale, Experimental Work, and Clinical Applications

“…This type of transfection resulted in temporary action, which offers a higher safety in case of adverse effects. Due to the transient effect, repeated infusions are needed for an optimal effect [58].…”