The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines

Abstract

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.

Simulating drug penetration during hyperthermic intraperitoneal chemotherapy

“…Extensive in vitro and in vivo experiments, varying chemotherapy and cell-line, are needed to investigate the entire spectrum of thermal enhancement for each cancer origin. Substantial in vitro data, combining various chemotherapies with various cell-lines, is presented in (Helderman et al., 2020 ), underlining the variability of the thermal enhancement of chemotherapies.…”

“…However, convection in the peritoneal cavity affects the drug delivery, which was not accounted for during this study. Furthermore, the thermal effect during HIPEC is expected to play a major role in the drug delivery, since temperature influences the cytotoxicity of the chemotherapy, the diffusivity and the tumor microenvironment (Helderman et al., 2019 , 2020 ). Other treatment parameters such as dose and velocity could also influence the drug distribution in the peritoneal cavity.…”

Image-Guided Radiofrequency Hyperthermia (RFH)-Enhanced Direct Chemotherapy of Hepatic Tumors: The Underlying Biomolecular Mechanisms

“…The increased cytotoxicity of DOX, when administered with heat, may be attributed to modulating the tumor physiology and microenvironment, due to the increase of heat-induced membrane permeability and concomitant cellular uptake, which thus increases drug accumulation within the tumor cells (11,12).…”

Hyperthermic Intraperitoneal Chemotherapy: A Critical Review

“…Of note, many of the in vitro studies that have aimed to establish thermal enhancement of chemotherapy have used temperatures, exposure times, and drug concentrations that are not clinically relevant or achievable. Helderman and coworkers recently performed a series of in vitro experiments using clinically relevant conditions (38-43 • C for 60 min) in several 2D and 3D human colorectal cancer cultures [34]. They showed that thermal enhancement of cytotoxicity is highly dependent on the cell line and on the drug used: thermal enhancement was evident for oxaliplatin and cisplatin, but not for mitomycin C, carboplatin, or 5-FU.…”