Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer

English version

Autoři: Viktor Sandblom ^aff001; Johan Spetz ^aff001; Emman Shubbar ^aff001; Mikael Montelius ^aff001; Ingun Ståhl ^aff001; John Swanpalmer ^aff001; Ola Nilsson ^aff003; Eva Forssell-Aronsson ^aff001
Působiště autorů: Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ^aff001; Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden ^aff002; Department of Pathology, Institute of Biomedicine, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ^aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225260

Souhrn

Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue ¹⁷⁷Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as ¹⁷⁷Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received ¹⁷⁷Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining ¹⁷⁷Lu-octreotate with gemcitabine in patients.

Klíčová slova:

Animal models – Cancer treatment – Mouse models – Adverse reactions – Immunohistochemistry techniques – Radiation therapy – Thyroid carcinomas – Somatostatin

Zdroje

1. Wells Jr SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma: the American Thyroid Association Guidelines Task Force on medullary thyroid carcinoma. Thyroid. 2015;25(6):567–610. doi: 10.1089/thy.2014.0335 25810047

2. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458. doi: 10.1038/363458a0 8099202

3. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375. doi: 10.1038/367375a0 7906866

4. Marsh DJ, Learoyd DL, Andrew SD, Krishnan L, Pojer R, Richardson AL, et al. Somatic mutations in the RET proto‐oncogene in sporadic medullary thyroid carcinoma. Clinical Endocrinology. 1996;44(3):249–57. doi: 10.1046/j.1365-2265.1996.681503.x 8729519

5. Pelizzo M, Boschin I, Bernante P, Toniato A, Piotto A, Pagetta C, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. European Journal of Surgical Oncology (EJSO). 2007;33(4):493–7. doi: 10.1016/j.ejso.2006.10.021 17125960

6. Machens M, Andreas, Hinze M, Raoul, Thomusch M, Oliver, Dralle M, Henning. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World Journal of Surgery. 2002;26(1):22–8. doi: 10.1007/s00268-001-0176-3 11898029

7. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006;107(9):2134–42. doi: 10.1002/cncr.22244 17019736

8. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli J, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. The Journal of Clinical Endocrinology & Metabolism. 2006;91(8):2892–9.

9. Mato E, Matías-Guiu X, Chico A, Webb SM, Cabezas R, Berná L, et al. Somatostatin and Somatostatin Receptor Subtype Gene Expression in Medullary Thyroid Carcinoma 1. The Journal of Clinical Endocrinology & Metabolism. 1998;83(7):2417–20.

10. Forssell-Aronsson E, Nilsson O, Benjegard SA, Kölby L, Bernhardt P, Mölne J, et al. (111)In-DTPA-D-Phe(1)-octreotide binding and somatostatin receptor subtypes in thyroid tumors. Journal of Nuclear Medicine. 2000;41(4):636. 10768564

11. Forssell-Aronsson E, Bernhardt P, Nilsson O, Tisell L-E, Wängberg B, Ahlman H. Biodistribution data from 100 patients iv injected with 111In-DTPA-D-Phe1-octreotide. Acta Oncologica. 2004;43(5):436–42. doi: 10.1080/02841860410030670 15360047

12. Iten F, Müller B, Schindler C, Rochlitz C, Oertli D, Mäcke HR, et al. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clinical Cancer Research. 2007;13(22):6696–702.

13. Forssell-Aronsson E, Spetz J, Ahlman H. Radionuclide therapy via SSTR: future aspects from experimental animal studies. Neuroendocrinology. 2013;97(1):86–98. doi: 10.1159/000336086 22572526

14. Hung WW, Wang CS, Tsai KB, Ou‐Yang F, Shin SJ, Hsiao PJ. Medullary thyroid carcinoma with poor differentiation and atypical radiographic pattern of metastasis. Pathology International. 2009;59(9):660–3. doi: 10.1111/j.1440-1827.2009.02423.x 19712135

15. Dadan J, Wołczyński S, Sawicki B, Chyczewski L, Azzadin A, Dziecioł J, et al. Preliminary evaluation of influence of gemcitabine (Gemzar) on proliferation and neuroendocrine activity of human TT cell line: immunocytochemical investigations. Folia Histochemica et Cytobiologica. 2001;39(2):187–8. 11374818

16. Pauwels B, Korst AE, Lardon F, Vermorken JB. Combined modality therapy of gemcitabine and radiation. The Oncologist. 2005;10(1):34–51. doi: 10.1634/theoncologist.10-1-34 15632251

17. Wardman P. Chemical radiosensitizers for use in radiotherapy. Clinical Oncology. 2007;19(6):397–417. doi: 10.1016/j.clon.2007.03.010 17478086

18. Shewach DS, Hahn TM, Chang E, Hertel LW, Lawrence TS. Metabolism of 2′, 2′-difluoro-2′-deoxycytidine and radiation sensitization of human colon carcinoma cells. Cancer Research. 1994;54(12):3218–23. 8205542

19. Lawrence TS, Chang EY, Hahn TM, Hertel LW, Shewach DS. Radiosensitization of pancreatic cancer cells by 2′, 2′-difluoro-2′-deoxycytidine. International Journal of Radiation Oncology • Biology • Physics. 1996;34(4):867–72.

20. Mason KA, Milas L, Hunter NR, Elshaikh M, Buchmiller L, Kishi K, et al. Maximizing therapeutic gain with gemcitabine and fractionated radiation. International Journal of Radiation Oncology • Biology • Physics. 1999;44(5):1125–35.

21. Milas L, Fujii T, Hunter N, Elshaikh M, Mason K, Plunkett W, et al. Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Research. 1999;59(1):107–14. 9892194

22. Pauwels B, Korst AE, Pattyn GG, Lambrechts HA, Van Bockstaele DR, Vermeulen K, et al. Cell cycle effect of gemcitabine and its role in the radiosensitizing mechanism in vitro. International Journal of Radiation Oncology • Biology • Physics. 2003;57(4):1075–83.

23. Blackstock AW, Bernard SA, Richards F, Eagle KS, Case LD, Poole ME, et al. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. Journal of Clinical Oncology. 1999;17(7):2208–. doi: 10.1200/JCO.1999.17.7.2208 10561277

24. Eisbruch A, Shewach DS, Bradford CR, Littles JF, Teknos TN, Chepeha DB, et al. Radiation concurrent with gemcitabine for locally advanced head and neck cancer: a phase I trial and intracellular drug incorporation study. Journal of Clinical Oncology. 2001;19(3):792–9. doi: 10.1200/JCO.2001.19.3.792 11157033

25. McGinn CJ, Zalupski MM, Shureiqi I, Robertson JM, Eckhauser FE, Smith DC, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. Journal of Clinical Oncology. 2001;19(22):4202–8. doi: 10.1200/JCO.2001.19.22.4202 11709563

26. Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, et al. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. Journal of Clinical Oncology. 2011;29(13):1678–85. doi: 10.1200/JCO.2009.25.9663 21444871

27. Loehrer PJ, Feng Y, Cardenes H, Wagner L, Brell JM, Cella D, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology. 2011;29(31):4105–12. doi: 10.1200/JCO.2011.34.8904 21969502

28. Johanson V, Ahlman H, Bernhardt P, Jansson S, Kölby L, Persson F, et al. A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis. Endocrine-Related Cancer. 2007;14(2):433–44. doi: 10.1677/ERC-06-0033 17639056

29. Bolch WE, Eckerman KF, Sgouros G, Thomas SR. MIRD pamphlet no. 21: a generalized schema for radiopharmaceutical dosimetry—standardization of nomenclature. Journal of Nuclear Medicine. 2009;50(3):477–84. doi: 10.2967/jnumed.108.056036 19258258

30. Miller WH, Hartmann-Siantar C, Fisher D, Descalle M-A, Daly T, Lehmann J, et al. Evaluation of beta-absorbed fractions in a mouse model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu radionuclides. Cancer Biotherapy & Radiopharmaceuticals. 2005;20(4):436–49.

31. Eckerman K, Endo A. ICRP Publication 107. Nuclear decay data for dosimetric calculations. Annals of the ICRP. 2008;38(3):7–96. doi: 10.1016/j.icrp.2008.10.004 19285593

32. Dalmo J, Rudqvist N, Spetz J, Laverman P, Nilsson O, Ahlman H, et al. Biodistribution of 177Lu-octreotate and 111In-minigastrin in female nude mice transplanted with human medullary thyroid carcinoma GOT2. Oncology Reports. 2012;27(1):174–81. doi: 10.3892/or.2011.1494 21993546

33. Holm S. A simple sequentially rejective multiple test procedure. Scandinavian Journal of Statistics. 1979:65–70.

34. Bliss C. The toxicity of poisons applied jointly. Annals of Applied Biology. 1939;26(3):585–615.

35. Yeh PJ, Hegreness MJ, Aiden AP, Kishony R. Drug interactions and the evolution of antibiotic resistance. Nature Reviews Microbiology. 2009;7(6):460–6. doi: 10.1038/nrmicro2133 19444248

36. Dalmo J, Spetz J, Montelius M, Langen B, Arvidsson Y, Johansson H, et al. Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1. EJNMMI Research. 2017;7(1):6. doi: 10.1186/s13550-016-0247-y 28097640

37. Montelius M, Spetz J, Jalnefjord O, Berger E, Nilsson O, Ljungberg M, et al. Identification of potential MR-derived biomarkers for tumor tissue response to 177Lu-octreotate therapy in an animal model of small intestine neuroendocrine tumor. Translational Oncology. 2018;11(2):193–204. doi: 10.1016/j.tranon.2017.12.003 29331677

38. Greco WR, Faessel H, Levasseur L. The search for cytotoxic synergy between anticancer agents: a case of Dorothy and the ruby slippers? Journal of the National Cancer Institute. 1996;88(11):699–700. doi: 10.1093/jnci/88.11.699 8637018

39. Palmer AC, Sorger PK. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell. 2017;171(7):1678–91. doi: 10.1016/j.cell.2017.11.009 29245013

40. Fueger BJ, Hamilton G, Raderer M, Pangerl T, Traub T, Angelberger P, et al. Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells. Journal of Nuclear Medicine. 2001;42(12):1856–62. 11752085

41. Nayak TK, Atcher RW, Prossnitz ER, Norenberg JP. Enhancement of somatostatin-receptor-targeted 177 Lu-[DOTA 0-Tyr 3]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation. Nuclear Medicine and Biology. 2008;35(6):673–8. doi: 10.1016/j.nucmedbio.2008.05.003 18678352

42. Matuszczyk A, Petersenn S, Voigt W, Kegel T, Dralle H, Schmoll H, et al. Chemotherapy with paclitaxel and gemcitabine in progressive medullary and thyroid carcinoma of the follicular epithelium. Hormone and Metabolic Research. 2010;42(01):61–4.

43. Full Prescribing Information for Gemcitabine Hydrochloride National Cancer Institute2018 [13 Mar 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf.

44. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy. 2016;7(2):27. doi: 10.4103/0976-0105.177703 27057123

45. Waldherr C, Schumacher T, Pless M, Crazzolara A, Maecke H, Nitzsche E, et al. Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using [90Y]-DOTA-D-Phe1-Tyr3-octreotide: a pilot study. Nuclear Medicine Communications. 2001;22(6):673–8. doi: 10.1097/00006231-200106000-00011 11403179

46. Bodei L, Handkiewicz-Junak D, Grana C, Mazzetta C, Rocca P, Bartolomei M, et al. Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas. Cancer Biotherapy and Radiopharmaceuticals. 2004;19(1):65–71. doi: 10.1089/108497804773391694 15068613

47. Makis W, McCann K, McEwan AJ. Medullary thyroid carcinoma (MTC) treated with 177Lu-DOTATATE PRRT: a report of two cases. Clinical Nuclear Medicine. 2015;40(5):408–12. doi: 10.1097/RLU.0000000000000706 25674858

48. Vaisman F, de Castro PHR, Lopes FPPL, Kendler DB, Pessoa CH, Bulzico DA, et al. Is there a role for peptide receptor radionuclide therapy in medullary thyroid cancer? Clinical Nuclear Medicine. 2015;40(2):123–7. doi: 10.1097/RLU.0000000000000628 25546220

49. Salavati A, Puranik A, Kulkarni HR, Budiawan H, Baum RP. Peptide receptor radionuclide therapy (PRRT) of medullary and nonmedullary thyroid cancer using radiolabeled somatostatin analogues. Seminars in Nuclear Medicine. 2016;46(3):215–24. doi: 10.1053/j.semnuclmed.2016.01.010 27067502

50. Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. European Journal of Nuclear Medicine and Molecular Imaging. 2015;42(1):5–19. doi: 10.1007/s00259-014-2893-5 25273832

51. Brabander T, Van der Zwan WA, Teunissen JJ, Kam BL, Feelders RA, de Herder WW, et al. Long-term efficacy, survival and safety of [177Lu-DOTA0, Tyr3] octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research. 2017;23(16):4617–24. doi: 10.1158/1078-0432.CCR-16-2743 28428192

52. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine. 2017;376(2):125–35. doi: 10.1056/NEJMoa1607427 28076709

Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer

Souhrn

Klíčová slova:

Zdroje

PLOS One

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Eozinofilní granulomatóza s polyangiitidou