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Effects of hyperthermia, chemotherapy and immunotherapy with interleukin-2 on survival rate of mice-bearing peritoneal carcinomatosis.

Background/aims: Peritoneal carcinomatosis is prognostically a very bad sign and common cause of death in patients with intestinal and stomach carcinoma as well as other gastrointestinal and gynecologic tumors. During a tumor surgery risk of peritoneal carcinomatosis is high because tumor cells are "dropping off" from the tumor surface which infiltrates serosa of abdominal cavity in which it has developed, so iatrogen peritoneal carcinomatosis develops. The aim of this study was to explore and compare different models of locoregional immunochemotherapy, hyperthermial intraperitonal chemotherapy (HIPEC) in unique animal model of induced peritoneal carcinomatosis in mice. Material and methods: CBA mice were injected with mammary carcinoma (MCa) cells into abdominal cavity and consecutive peritoneal carcinomatosis was induced. In so called prevention model biological response modifiers (BRM), interleukin-2 (IL-2) at dose of 4.1 x 104 IU/mouse was injected into abdominal cavity seven and three days before injection of tumor cells, respectively. Immediately after the injection of tumor cells we rinsed abdominal cavity with saline that was heated to 37°C or 43°C (hyperthermial treatment) and injected cytostatics: doxorubicin (DOX) 20 mg kg-1, cisplatin (CIS) 10 mg kg-1, mitomicyn (MIT) 5 mg kg-1, 5- fluorouracil (5-FU) 150 mg kg-1 either separately or in combination. In therapeutic model cytostatics were injected on day 5th after injection of tumor cells. Hyperthermia treatment was performed immediately before injection of cytostatic drugs. Results: Results of these studies showed significant difference in surviving time (engl. increased life span ; ILS%) of mice pretreated with IL-2 and treated with hyperthermic chemotherapy compared with control: IL-2+ CIS (ILS%=260, 50) ; IL-2+ DOX + CIS (ILS%=200) ; IL-2 + MIT (ILS%=178, 05) ; IL-2 + CDL (ILS%=70, 20) ; IL-2+ DOX (ILS%=67, 92) ; IL-2 + 5-FU (ILS%=62, 69) ; IL-2+ 5-FU+ DOX (ILS%=55, 22). Treatment of mice with IL-2+ 5-FU+ CIS was toxic to mice ; all mice died before control group. Conclusion: The results suggest the synergistic effect of hyperthermia, chemotherapy and immunotherapy ; IL-2 significantly increase antitumor activity of hyperthermic chemotherapy and survival rate of mice with peritoneal carcinomatosis. It is likely that stimulative effect of IL-2 on hematopoiesis, differentiation and proliferation on stem cells as well as immunomodulation may be possible mechanism which protect mice from development of peritoneal carcinomatosis and reduce side effect of chemotherapy treatment increasing life spin of mice. However, the exact antitumor mechanism mechanisms of hyperthermic chemoimmunotheraphy effectiveness have to be elucidated.

Peritoneal carcinomatosis; IL-2; Hyperthermia; Chemotheraphy; Immunomodulation

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