Comparing the cytotoxicity of taurolidine, mitomycin C, and oxaliplatin on the proliferation of in vitro colon carcinoma cells following pressurized intra-peritoneal aerosol chemotherapy (PIPAC)

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Abstract

Background

Besides its known antibacterial effect commonly used in intraperitoneal lavage, taurolidine has been observed to possess antineoplastic properties. In order to analyse this antineoplastic potential in a palliative therapeutic setting, taurolidine (TN) was compared to mitomycin C (MMC) and oxaliplatin (OX), known antineoplastic agents which are routinely used in intraperitoneal applications, following pressurized intra-peritoneal aerosol chemotherapy (PIPAC).

Methods

An in vitro model was established using a colon adenocarcinoma cell line (HT-29 human cells). Different experimental dosages of TN and combinations of TN, MMC, and OX were applied via PIPAC. To measure cell proliferation, a colorimetric tetrazolium reduction assay was utilized 24 h after PIPAC.

Results

We demonstrated a cytotoxic effect of TN and OX (184 mg/150 mL, p < 0.01) on tumor cell growth. An increasing dosage of TN (from 0.5 g/100 mL to 0.75 g/150 mL) correlated with higher cell toxicity when compared to untreated cells ( p < 0.05 and p < 0.01, respectively). PIPAC with OX and both OX and TN (0.5 g/100 mL) showed the same cytotoxic effect ( p < 0.01). No significant impact was observed for MMC (14 mg/50 mL, p > 0.05) or MMC with OX ( p > 0.05) applied via PIPAC.

Conclusions

The intraperitoneal application of TN is mostly limited to lavage procedures in cases of peritonitis. Our results indicate a substantial antineoplastic in vitro effect on colon carcinoma cells following PIPAC application. While this effect could be used in the palliative treatment of peritoneal metastases, further clinical studies are required to investigate the feasibility of TN application in such cases.

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Most cited references 24

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Description of a novel approach for intraperitoneal drug delivery and the related device.

A Reymond, Alexander Hetzel, Emil Sagynaliev … (2012)

Two significant limitations of intraperitoneal drug therapy are limited drug distribution and poor penetration into peritoneal nodules. A possible solution is the application of the so-called "therapeutic pneumoperitoneum," taking advantage of the gaseous nature and the pressure of capnoperitoneum during laparoscopy. Our objective was to develop a device able to apply such therapeutic pneumoperitoneum. The technology presented here is a spraying device and can be introduced through a trocar. It is driven by mechanical pressure and consists of an injector, a line, and a nozzle. An in vivo experimental study was performed in five pigs. A transvaginal cholecystectomy was performed. At the end of the procedure, a standard dose of methylene blue was sprayed/infused into the abdominal cavity for 30 min (4 test animals w/therapeutic pneumoperitoneum (12 mmHg CO(2)) and 1 control animal w/conventional lavage (2 l intra-abdominal volume with extracorporeal circulation)). At the end of the procedure, all animals were autopsied and the peritoneum was analyzed. Outcome criteria were: (1) drug distribution (as assessed by the stained peritoneal surface at autopsy), and (2) diffusion into the peritoneum (presence or not of macroscopic staining of the outer aspect of the peritoneum immediately after surgery). Stained peritoneal surface was larger after aerosol application compared with peritoneal lavage, and staining more intense. Hidden peritoneal surfaces and the anterior abdominal wall were stained only in the aerosol group. In contrast to peritoneal lavage, the outer aspect of peritoneal membrane was immediately stained after pressurized spraying. This device and the related approach significantly improve both distribution and penetration of a test substance into the peritoneal cavity in a large animal model. This might be a significant progress in treating intraperitoneal disease, in particular peritoneal carcinomatosis.

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Intraperitoneal therapy for peritoneal cancer.

Ze Lu, Jie Wang, M. Guillaume Wientjes … (2010)

Cancers originating from organs in the peritoneal cavity (e.g., ovarian, pancreatic, colorectal, gastric and liver) account for approximately 250,000 new cancer cases annually in the USA. Peritoneal metastases are common owing to locoregional spread and distant metastases of extraperitoneal cancers. A logical treatment is intraperitoneal therapy, as multiple studies have shown significant targeting advantage for this treatment, including significant survival benefits in stage III, surgically debulked ovarian cancer patients. However, the clinical use of intraperitoneal therapy has been limited, in part, by toxicity, owing to the use of indwelling catheters or high drug exposure, by inadequate drug penetration into bulky tumors (>1 cm) and by the lack of products specifically designed and approved for intraperitoneal treatments. This article provides an overview on the background of peritoneal metastasis, clinical research on intraperitoneal therapy, the pharmacokinetic basis of drug delivery in intraperitoneal therapy and our development of drug-loaded tumor-penetrating microparticles.

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Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy.

D M Kweekel, H Gelderblom, H.-J. Guchelaar (2005)

Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another. There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer.

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Author and article information

Contributors

Justyna Schubert:

ORCID: http://orcid.org/0000-0002-5703-5787

+ 048-(71)-320-5262 , justyna.schubert@upwr.edu.pl

Veria Khosrawipour: veriakhosrawipour@yahoo.de

Haris Chaudhry: hhchaudh@uci.edu

Mohamed Arafkas: arafkasm@esv.de

Wolfram Trudo Knoefel: WolframTrudo.Knoefel@med.uni-duesseldorf.de

Alessio Pigazzi: apigazzi@uci.edu

Tanja Khosrawipour: tanja.khosrawipour@rub.de

Journal

Journal ID (nlm-ta): World J Surg Oncol

Journal ID (iso-abbrev): World J Surg Oncol

Title: World Journal of Surgical Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-7819

Publication date (Electronic): 3 June 2019

Publication date PMC-release: 3 June 2019

Publication date Collection: 2019

Volume: 17

Electronic Location Identifier: 93

Affiliations

[1 ]Department of Food Hygiene and Consumer Health Protection, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland

[2 ]Department of Orthopedic and Trauma Surgery, Ortho-Klinik Dortmund, Dortmund, Germany

[3 ]Division of Colorectal Surgery, Department of Surgery, University of California Irvine (UCI), California, USA

[4 ]Department of Plastic Surgery, Ortho-Klinik Dortmund, Dortmund, Germany

[5 ]ISNI 0000 0000 8922 7789, GRID grid.14778.3d, Department of Surgery (A), , University-Hospital Düsseldorf, ; Düsseldorf, Germany

Author information

Justyna Schubert http://orcid.org/0000-0002-5703-5787

Article

Publisher ID: 1633

DOI: 10.1186/s12957-019-1633-5

PMC ID: 6547564

PubMed ID: 31159819

SO-VID: 646983e2-82e9-4b51-941a-102f4945e390

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 March 2019

Date accepted : 20 May 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004569, Ministerstwo Nauki i Szkolnictwa Wyższego;

Award ID: 0019/SDU/2018/18

Award Recipient : Justyna Schubert

Funded by: University of California Irvine

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ScienceOpen disciplines: Surgery

Keywords: colon carcinoma,pressurized intra-peritoneal aerosol chemotherapy (pipac),peritoneal metastasis,taurolidine,mitomycin c,oxaliplatin

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ScienceOpen disciplines: Surgery

Keywords: colon carcinoma, pressurized intra-peritoneal aerosol chemotherapy (pipac), peritoneal metastasis, taurolidine, mitomycin c, oxaliplatin

Comparing the cytotoxicity of taurolidine, mitomycin C, and oxaliplatin on the proliferation of in vitro colon carcinoma cells following pressurized intra-peritoneal aerosol chemotherapy (PIPAC)

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Most cited references 24

Description of a novel approach for intraperitoneal drug delivery and the related device.

Intraperitoneal therapy for peritoneal cancer.

Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy.

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