Increasing the efficiency of hyperthermic intraperitoneal chemotherapy (HIPEC) by combination with a photosensitive drug in pediatric rhabdomyosarcoma in an animal model

Abstract

Background Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is an option in advanced peritoneal sarcomatosis. Nevertheless, CRS and HIPEC are not successful in all patients. An enhancement of HIPEC using photodynamic therapy (PDT) might be beneficial. Therefore, a combination of the photosensitizer hypericin (HYP) with HIPEC was evaluated in an animal model. Procedure An established HIPEC animal model for rhabdomyosarcoma (NOD/LtSz‐scid IL2Rγnullmice, n = 80) was used. All groups received HYP (100 μg/200 μl) intraperitoneally with and without cisplatin‐based (30 or 60 mg/m2) HIPEC (37°C or 42°C, for 60 minutes) (five groups, each n = 16). Peritoneal cancer index (PCI) was documented visually and by HYP‐based photodynamic diagnosis (PDD). HYP‐based PDT of the tumor was performed. Tissue samples were evaluated regarding proliferation (Ki‐67) and apoptosis (TUNEL). Results HYP uptake was detected even in smallest tumor nodes (<1 mm) with improved tumor detection during PDD (PCI with PDD vs. PCI without PDD: 8.5 vs. 7, p < .001***). Apoptotic effects after PDT without HIPEC were limited to the tumor surface, whereas PDT after HIPEC (60 mg/m2, 42°C) showed additional reduction of tumor proliferation in the top nine to 11 cell layers (50 μm). Conclusion HYP as fluorescent photosensitizer offers an intraoperative diagnostic advantage detecting intraperitoneal tumor dissemination. The combination of HYP and cisplatin‐based HIPEC was feasible in vivo, showing enhanced effects on tumor proliferation and apoptosis induction across the tumor surface. Further studies combining HYP and HIPEC will follow to establish a clinical application.

Contemporary preclinical mouse models for pediatric rhabdomyosarcoma: from bedside to bench to bedside

“…Of interest, the RH30 cell line is derived from the bone marrow metastasis of a 16-year-old male of untreated aRMS (28). In our sample, this cell line was used to establish different RMS phenotypes including peritoneal sarcomatosis (29), orthotopicCDX (30), ectopicCDX (31), or metastatic CDX model by intravenous cell injection (32). The question arises as to whether cell cultures derived from metastatic origins can accurately represent the behavior of the primary tumor in a mouse model.…”

“…Among them, 37.5% of studies were able to induce metastasis spontaneously using GEMM (20,27), orthotopic CDX (71,72) or even ectopic xenografts (73), all of which disseminated to the lungs. Another approach to inducing metastases was through the injection of tumor cells, either intravenously (tail vein murine models), resulting in lung (24,(74)(75)(76)(77)(78), bone marrow (32), and liver/spleen (79) metastasis, or intraperitoneally, resulting in peritoneal sarcomatosis (xenograft models with intraperitoneal dissemination) (29,(80)(81)(82).…”

Fluorescence-Guided Laparoscopy after Oral Hypericin Administration for Staging of Locally Advanced Gastric Cancer—A Pilot Study

“…Another potential method of hypericin administration would obviously be intravenous or even local application into the peritoneal cavity, which might circumvent pharmacokinetic issues. The feasibility of intra-abdominal application of hypericin to enhance tumor detection has been demonstrated recently in an animal model of peritoneal metastasis [54]. Nevertheless, hypericin is not an approved drug for intravenous or intra-abdominal use and is so far unavailable.…”

A Review of the Use of Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy in Pediatric Patients

“…One group has developed an animal model of HIPEC for alveolar RMS where they are able to measure an adapted PCI, alter HIPEC conditions and timing, and measure tumor apoptosis, although their ethics committee did not allow them to conduct CRS prior to HIPEC, limiting the utility of the model [66]. They followed up these initial studies with the evaluation of photodynamic therapy and the photosensitizer hypericin, an extract from St. John's wort, in addition to cisplatin HIPEC in the same animal mouse model and demonstrated additional reduction of tumor proliferation [67]. It is additionally useful in its ability to allow better identification of the tumor tissue it is killing, down to tumors less than 1 mm, and will be a promising system to bring to humans after additional study.…”