The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines
Roxan F.C.P.A. Helderman,
Daan R. Löke,
Jan Verhoeff,
Hans M. Rodermond,
Gregor G.W. van Bochove,
Menno Boon,
Sanne van Kesteren,
Juan J. Garcia Vallejo,
H. Petra Kok,
Pieter J. Tanis,
Nicolaas A.P. Franken,
Johannes Crezee,
Arlene L. Oei
Affiliations
Roxan F.C.P.A. Helderman
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Daan R. Löke
Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Jan Verhoeff
Department of Molecular Cell Biology & Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
Hans M. Rodermond
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Gregor G.W. van Bochove
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Menno Boon
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Sanne van Kesteren
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Juan J. Garcia Vallejo
Department of Molecular Cell Biology & Immunology, Amsterdam Infection & Immunity Institute and Cancer Center Amsterdam, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
H. Petra Kok
Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Pieter J. Tanis
Department for Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Nicolaas A.P. Franken
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Johannes Crezee
Department of Radiation Oncology, Amsterdam UMC, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Arlene L. Oei
Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam University Medical Centers (UMC), University of Amsterdam, Cancer Center Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC. Methods: The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38–43 °C/60 min). Results: Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat. Conclusion: Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC.
