TY - JOUR
T1 - The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines
AU - Helderman, Roxan F.C.P.A.
AU - Löke, Daan R.
AU - Verhoeff, Jan
AU - Rodermond, Hans M.
AU - van Bochove, Gregor G.W.
AU - Boon, Menno
AU - van Kesteren, Sanne
AU - Garcia Vallejo, Juan J.
AU - Kok, H. Petra
AU - Tanis, Pieter J.
AU - Franken, Nicolaas A.P.
AU - Crezee, Johannes
AU - Oei, Arlene L.
N1 - Copyright: This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2020/7/25
Y1 - 2020/7/25
N2 - 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.
AB - 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.
KW - 5-fluorouracil
KW - HIPEC
KW - colorectal cancer
KW - hyperthermia
KW - hyperthermic intraperitoneal chemotherapy
KW - mitomycin-C
KW - platinum-based drugs
UR - http://www.scopus.com/inward/record.url?scp=85088812502&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells9081775
DO - https://doi.org/10.3390/cells9081775
M3 - Article
C2 - 32722384
SN - 2073-4409
VL - 9
JO - Cells
JF - Cells
IS - 8
ER -