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,Johannes Crezee,Arlene L Oei,Hans M Rodermond,Gregor G.W Van Bochove,Daan R Löke,Menno Boon,Pieter J Tanis,Sanne Van Kesteren,Nicolaas A.P Franken,H Petra Kok,Juan J Garcia Vallejo,Jan Verhoeff

doi:10.3390/cells9081775

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.

Highlights

Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.2 million new cases each year [1,2]
Our data demonstrate that platinum-based drugs are effective for colorectal cancer (CRC) at temperatures above 41 ◦ C, suggesting that they are, in principle, suitable for use during hyperthermic intraperitoneal chemotherapy (HIPEC), which is always performed at more elevated temperatures
In our in vitro study, we demonstrate that platinum-based drugs and MMC are effective drugs for CRC cells and could be suitable for HIPEC, even when hyperthermia does not sensitize MMC in an in vitro setting (Figure 6)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.2 million new cases each year [1,2]. In 5–10% of patients diagnosed with CRC, peritoneal metastases (PMCRC) are already present and the incidence increases to 20–60% in recurrent disease [4,5]. PMCRC is associated with poor prognosis, averaging only 5–24 months and a 5-year survival rate between 0 and 22% [6,7]. For these patients, the only effective treatment with curative intent is cytoreductive surgery (CRS). During HIPEC, the chemotherapeutic solution heated to 40–43 ◦ C is circulated through the peritoneum for a period of 30 min, and up to 2 h [8,9]

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