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Open Access 01-10-2021 | Ionizing Radiation | Original Article

Dose-dependence of radiotherapy-induced changes in serum levels of choline-containing phospholipids; the importance of lower doses delivered to large volumes of normal tissues

Authors: Karol Jelonek, Aleksandra Krzywon, Katarzyna Papaj, Pawel Polanowski, Krzysztof Szczepanik, Krzysztof Skladowski, Piotr Widlak

Published in: Strahlentherapie und Onkologie | Issue 10/2021

Abstract

Background

Conformal radiotherapy is a primary treatment in head and neck cancer, which putative adverse effects depend on relatively low doses of radiation delivered to increased volumes of normal tissues. Systemic effects of such treatment include radiation-induced changes in serum lipid profile, yet dose- and volume-dependence of these changes remain to be established.

Methods

Here we analyzed levels of choline-containing phospholipids in serum samples collected consecutively during the radiotherapy used as the only treatment modality. The liquid chromatography–mass spectrometry (LC-MS) approach applied in the study enabled the detection and quantitation of 151 phospholipids, including (lyso)phosphatidylcholines and sphingomyelins.

Results

No statistically significant differences were found in the pretreatment samples from patients with different locations and stages of cancer. To compensate for potential differences between schemes of radiotherapy, the biologically effective doses were calculated and used in the search of correlations with specific lipid levels. We found that the levels of several phospholipids depended on the maximum dose delivered to the gross tumor volume and total radiation energy absorbed by the patient’s body. Increased doses correlated with increased levels of sphingomyelins and reduced levels of phosphatidylcholines. Furthermore, we observed several phospholipids whose serum levels correlated with the degree of acute radiation toxicity.

Conclusion

Noteworthy, serum phospholipid levels were associated mainly with volumes of normal tissues irradiated with relatively low doses (i.e., total accumulated dose 20 Gy), which indicated the importance of such effects on the systemic response of the patient’s organism to intensity-modulated radiotherapy (IMRT).

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Gupta B, Johnson NW, Kumar N (2016) Global epidemiology of head and neck cancers: a continuing challenge. Oncology 91(1):13–23. https://doi.org/10.1159/000446117CrossRefPubMed

Cmelak AJ (2012) Current issues in combined modality therapy in locally advanced head and neck cancer. Crit Rev Oncol Hematol 84(2):261–273. https://doi.org/10.1016/j.critrevonc.2012.04.004CrossRefPubMed

Lin C, Donaldson SS, Meza JL, Anderson JR, Lyden ER, Brown CK, Morano K, Laurie F, Arndt CA, Enke CA, Breneman JC (2012) Effect of radiotherapy techniques (IMRT vs. 3D-CRT) on outcome in patients with intermediate-risk rhabdomyosarcoma enrolled in COG D9803—a report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 82(5):1764–1770. https://doi.org/10.1016/j.ijrobp.2011.01.036CrossRefPubMed

Abel E, Silander E, Nyman J, Björk-Eriksson T, Hammerlid E (2020) Long-term aspects of quality of life in head and neck cancer patients treated with intensity modulated radiation therapy: a 5‑year longitudinal follow-up and comparison with a normal population cohort. Adv Radiat Oncol 5(1):101–110. https://doi.org/10.1016/j.adro.2019.07.015CrossRefPubMed

González Ferreira JA, Jaén Olasolo J, Azinovic I, Jeremic B (2015) Effect of radiotherapy delay in overall treatment time on local control and survival in head and neck cancer: review of the literature. Rep Pract Oncol Radiother 20(5):328–339. https://doi.org/10.1016/j.rpor.2015.05.010CrossRefPubMedPubMedCentral

Bese NS, Hendry J, Jeremic B (2007) Effects of prolongation of overall treatment time due to unplanned interruptions during radiotherapy of different tumor sites and practical methods for compensation. Int J Radiat Oncol Biol Phys 68(3):654–661. https://doi.org/10.1016/j.ijrobp.2007.03.010CrossRefPubMed

Story MD, Durante M (2018) Radiogenomics. Med Phys 45(11):e1111–e1122. https://doi.org/10.1002/mp.13064CrossRefPubMed

Wu H, Yu J, Kong D, Xu Y, Zhang Z, Shui J, Li Z, Luo H, Wang K (2019) Population and single-cell transcriptome analyses reveal diverse transcriptional changes associated with radioresistance in esophageal squamous cell carcinoma. Int J Oncol 55(6):1237–1248. https://doi.org/10.3892/ijo.2019.4897CrossRefPubMedPubMedCentral

Jelonek K, Pietrowska M, Widlak P (2017) Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity. Int J Radiat Biol 93(7):683–696. https://doi.org/10.1080/09553002.2017.1304590CrossRefPubMed

10.

Widłak P, Pietrowska M, Polańska J, Rutkowski T, Jelonek K, Kalinowska-Herok M, Gdowicz-Kłosok A, Wygoda A, Tarnawski R, Składowski K (2013) Radiotherapy-related changes in serum proteome patterns of head and neck cancer patients; the effect of low and medium doses of radiation delivered to large volumes of normal tissue. J Transl Med 11:299. https://doi.org/10.1186/1479-5876-11-299CrossRefPubMedPubMedCentral

11.

Widlak P, Jelonek K, Wojakowska A, Pietrowska M, Polanska J, Marczak L, Miszczyk L, Skladowski K (2015) Serum Proteome signature of radiation response: upregulation of inflammation-related factors and downregulation of Apolipoproteins and coagulation factors in cancer patients treated with radiation therapy—A pilot study. Int J Radiat Oncol Biol Phys 92(5):1108–1115. https://doi.org/10.1016/j.ijrobp.2015.03.040CrossRefPubMed

12.

Jelonek K, Krzywon A, Jablonska P, Slominska EM, Smolenski RT, Polanska J, Rutkowski T, Mrochem-Kwarciak J, Skladowski K, Widlak P (2020) Systemic effects of radiotherapy and concurrent chemo-radiotherapy in head and neck cancer patients-comparison of serum metabolome profiles. Metabolites 10(2):60. https://doi.org/10.3390/metabo10020060CrossRefPubMedCentral

13.

Dennis EA (2009) Lipidomics joins the omics evolution. Proc Natl Acad Sci USA 106(7):2089–2090. https://doi.org/10.1073/pnas.0812636106CrossRefPubMedPubMedCentral

14.

Fagone P, Jackowski S (2013) Phosphatidylcholine and the CDP-choline cycle. Biochim Biophys Acta 1831(3):523–532. https://doi.org/10.1016/j.bbalip.2012.09.009CrossRefPubMed

15.

Kolesnick R (1994) Signal transduction through the sphingomyelin pathway. Mol Chem Neuropathol 21(2):287–297. https://doi.org/10.1007/BF02815356CrossRefPubMed

16.

Jagannathan NR, Kumar M, Seenu V, Coshic O, Dwivedi SN, Julka PK, Srivastava A, Rath GK (2001) Evaluation of total choline from in-vivo volume localized proton MR spectroscopy and its response to neoadjuvant chemotherapy in locally advanced breast cancer. Br J Cancer 84(8):1016–1022. https://doi.org/10.1054/bjoc.2000.1711CrossRefPubMedPubMedCentral

17.

Xi C, Zhao H, Lu X, Cai TJ, Li S, Liu KH, Tian M, Liu QJ (2020) Screening of lipids for early triage and dose estimation after acute radiation exposure in rat plasma based on targeted lipidomics analysis. J Proteome Res. https://doi.org/10.1021/acs.jproteome.0c00560CrossRefPubMed

18.

Jelonek K, Pietrowska M, Ros M, Zagdanski A, Suchwalko A, Polanska J, Marczyk M, Rutkowski T, Skladowski K, Clench MR, Widlak P (2014) Radiation-induced changes in serum lipidome of head and neck cancer patients. Int J Mol Sci 15(4):6609–6624. https://doi.org/10.3390/ijms15046609CrossRefPubMedPubMedCentral

19.

Hajduk A, Składowski K, Boguszewicz Ł, Mrochem-Kwarciak J, Hutnik M, Lukaszczyk-Wideł B, Rutkowski T, Wygoda A, Przeorek W, Golen M, Pilecki B, Sokol M, Maslyk B (2012) Acute radiaton sequel evaluaton in head and neck cancer patents. A new concept of comprehensive scoring system—multiparametric monitoring. Eur Arch Otorhinolaryngol. https://doi.org/10.1007/s00405-012-1960-4CrossRef

20.

Bentzen SM, Dörr W, Gahbauer R, Howell RW, Joiner MC, Jones B, Jones DT, van der Kogel AJ, Wambersie A, Whitmore G (2012) Bioeffect modeling and equieffective dose concepts in radiation oncology—terminology, quantities and units. Radiother Oncol 105(2):266–268. https://doi.org/10.1016/j.radonc.2012.10.006CrossRefPubMed

21.

Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226(1):497–509CrossRef

22.

Mukaka MM (2012) Statistics corner: A guide to appropriate use of correlation coefficient in medical research. Malawi Med J 24(3):69–71PubMedPubMedCentral

23.

Zahnreich S, Ebersberger A, Kaina B, Schmidberger H (2015) Biodosimetry based on γ‑H2AX quantification and cytogenetics after partial- and total-body irradiation during fractionated radiotherapy. Radiat Res 183(4):432–446. https://doi.org/10.1667/rr13911.1CrossRefPubMed

24.

O’Brien G, Cruz-Garcia L, Majewski M, Grepl J, Abend M, Port M, Tichý A, Sirak I, Malkova A, Donovan E, Gothard L, Boyle S, Somaiah N, Ainsbury E, Ponge L, Slosarek K, Miszczyk L, Widlak P, Green E, Patel N, Kudari M, Gleeson F, Vinnikov V, Starenkiy V, Artiukh S, Vasyliev L, Zaman A, Badie C (2018) FDXR is a biomarker of radiation exposure in vivo. Sci Rep 8(1):684. https://doi.org/10.1038/s41598-017-19043-wCrossRefPubMedPubMedCentral

25.

Marples B, Collis SJ (2008) Low-dose hyper-radiosensitivity: past, present, and future. Int J Radiat Oncol Biol Phys 70(5):1310–1318. https://doi.org/10.1016/j.ijrobp.2007.11.071CrossRefPubMed

26.

Aloulou A, Rahier R, Arhab Y, Noiriel A, Abousalham A (2018) Phospholipases: an overview. Methods Mol Biol 1835:69–105. https://doi.org/10.1007/978-1-4939-8672-9_3CrossRefPubMed

27.

Huang YH, Schäfer-Elinder L, Wu R, Claesson HE, Frostegård J (1999) Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. Clin Exp Immunol 116(2):326–331. https://doi.org/10.1046/j.1365-2249.1999.00871.xCrossRefPubMedPubMedCentral

28.

Taylor LA, Arends J, Hodina AK, Unger C, Massing U (2007) Plasma lyso-phosphatidylcholine concentration is decreased in cancer patients with weight loss and activated inflammatory status. Lipids Health Dis 6:17. https://doi.org/10.1186/1476-511x-6-17CrossRefPubMedPubMedCentral

29.

Green DR (2000) Apoptosis and sphingomyelin hydrolysis. The flip side. J Cell Biol 150(1):F5–F7. https://doi.org/10.1083/jcb.150.1.f5CrossRefPubMed

Title: Dose-dependence of radiotherapy-induced changes in serum levels of choline-containing phospholipids; the importance of lower doses delivered to large volumes of normal tissues
Authors: Karol Jelonek
Aleksandra Krzywon
Katarzyna Papaj
Pawel Polanowski
Krzysztof Szczepanik
Krzysztof Skladowski
Piotr Widlak
Publication date: 01-10-2021
Publisher: Springer Berlin Heidelberg
Keywords: Ionizing Radiation
Radiotherapy
Published in: Strahlentherapie und Onkologie / Issue 10/2021
Print ISSN: 0179-7158
Electronic ISSN: 1439-099X
DOI: https://doi.org/10.1007/s00066-021-01802-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Dose-dependence of radiotherapy-induced changes in serum levels of choline-containing phospholipids; the importance of lower doses delivered to large volumes of normal tissues

Abstract

Background

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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