New mechanisms of clinical efficacy of low-dose metronomic chemotherapy treatment of patients with metastatic colorectal cancer

Kudryavets Yu.I.1, Bezdenezhnykh N.O.2, Maksimyak G.I.3, Zhylchuk V.E.4, Adamenko I.M.2, Semesiuk N.2, Vorontsova A.L.2, Sichkoriz O.E.4, Chekhun V.F.2

Yu.I. Kudryavets1, N.O. Bezdenezhnykh1, G.I. Maksim’yak2, V.E. Zhylchuk2,3, I.M. Adamenko1, N.I. Semesiuk1, A.L. Vorontsova1, O.E. Sichkoriz3, V.F. Chekhun1

1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology NAS of Ukraine, Kyiv, Ukraine

2Rivne Region Oncology Hospital, Rivne, Ukraine

3Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

Background and Aim: This work describes the experience of treatment of metastatic colorectal cancer (mCRC) patients with liver metastases (stages T1–4N0–2M1) by low-dose chemotherapy (LDCT) in metronomic regimen including interferon-alpha (IFN), and demonstrates growth behavior and immunophenotypical changes in CRC cells after influence of LDCT in vitroPatients and Methods: Treatment of 254 patients was carried out using different schemes, which included cyclophosphamide, cisplatin (CP) and irinotecan (IT) with IFN, efficiency of therapy was monitored by clinical methods and computer tomography. Cell culture and immunocytochemical methods were used for in vitro investigation. Statistical analysis using the Student’s t-test and Kaplan — Meier survival curvesResultsMetronomic mode of LDCT in patients with mCRC demonstrated high performance compared with conventional treatment using only high dose of IT. Among the most effective schemes metronomic mode of application of LDCP and IT combination was shown: duration of partial clinical effect was nearly 3 fold higher, duration of the stabilization process and the overall survival rate increased respectively by 81% and 34.5% in comparison with a high dose IT therapy. Using of IFN in all the metronomic CT schemes significantly increased their effectiveness. We have found new targets in the CRC cells for the effects of LDCT in vitro. Cells of human colorectal adenocarcinoma of COLO 205 line were cultivated in vitro with LD (10–20 times lower IC50) of IT, CP, IFN and their combination for 30 days. The ability of cells after prolonged exposure by LDCT to the agar colony formation decreased by 3–5 times, the maximal effect was observed with the combination of IT + CP + IFN (from 9.25% to 0,25%). A significant decrease of number of cells with mesenchymal and malignant stem cell characteristics was found: number of N-cadherin-, SLUG- and CD44-positive cells decreased more than 10 fold for various combinations of drugs. Expression of ERCC1 marker in COLO 205 cells completely disappeared in all combinations with IFN, but increased somewhat under the influence of IT + CP. At the same time sensitivity of this cells to drugs in IC50 doses didn’t change. ConclusionsLow-dose metronomic chemotherapy of patients with mCRC is a new and perspective approach that provides suppression of the disease progression. LDCT drugs inhibit signs of epithelial-mesenchymal transition and malignant phenotype in CRC cells in vitro.

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