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In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines

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Abstract

Introduction

Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines.

Methods

Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay.

Results

With exception of the highly chemoresistant UMC-11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7–8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC-11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4–2.4-fold.

Conclusion

The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.

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References

  1. Öberg K (2003) Diagnosis and treatment of carcinoid tumors. Expert Rev Anticancer Ther 3:863–877

    Article  PubMed  Google Scholar 

  2. Modlin IM, Kidd M, Latich I et al (2005) Current status of gastrointestinal carcinoids. Gastroenterology 128:1717–1751

    Article  PubMed  Google Scholar 

  3. Pinchot SN, Holen K, Sippel RS, Chen H (2008) Carcinoid tumors. Oncologist 13:1255–1269

    Article  CAS  PubMed  Google Scholar 

  4. Zuetenhorst JM, Taal BG (2005) Metastatic carcinoid tumors: a clinical review. Oncologist 10:123–131

    Article  PubMed  Google Scholar 

  5. Granberg D, Oberg K (2005) Neuroendocrine tumours. Cancer Chemother Biol Response Modif 22:471–483

    PubMed  Google Scholar 

  6. Capella C, Heitz PU, Hofler H et al (1995) Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Virchows Arch 425:547–560

    Article  CAS  PubMed  Google Scholar 

  7. Warren WH, Gould VE, Faber LP et al (1985) Neuroendocrine neoplasms of the bronchopulmonary tract: a classification of the spectrum of carcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg 89:819–825

    CAS  PubMed  Google Scholar 

  8. Plockinger U, Rindi G, Arnold R et al (2004) European Neuroendocrine Tumour Society: guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80:394–424

    Article  CAS  PubMed  Google Scholar 

  9. Öberg K, Eriksson B (2005) Nuclear medicine in the detection, staging and treatment of gastrointestinal carcinoid tumours. Best Pract Res Clin Endocrinol Metab 19:265–276

    Article  PubMed  Google Scholar 

  10. Dousset B, Saint-Marc O, Pitre J et al (1996) Metastatic endocrine tumors: medical treatment, surgical resection and liver transplantation. World J Surg 20:908–915

    Article  CAS  PubMed  Google Scholar 

  11. Raderer M, Kurtaran A, Leimer M et al (2000) Value of peptide receptor scintigraphy using (123) I-vasoactive intestinal peptide and (111)In-DTPAD-Phe1-octreotide in 194 carcinoid patients: Vienna University Experience, 1993 to 1998. J Clin Oncol 18:1331–1336

    CAS  PubMed  Google Scholar 

  12. Smolle-Juttner FM, Popper H, Klemen H et al (1993) Clinical features and therapy of “typical” and “atypical” bronchial carcinoid tumors (grade 1 and grade 2 neuroendocrine carcinoma). Eur J Cardiothorac Surg 7:121–125

    Article  CAS  PubMed  Google Scholar 

  13. Marty-Ane CH, Costes V, Pujol JL et al (1995) Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg 59:78–83

    Article  CAS  PubMed  Google Scholar 

  14. Moertel CG, Sauer WG, Dockerty MB, Baggenstoss AH (1961) Life history of the carcinoid tumor of the small intestine. Cancer 14:901–912

    Article  CAS  PubMed  Google Scholar 

  15. Goodwin JD (1975) Carcinoid tumors: an analysis of 2837 cases. Cancer 36:560–569

    Article  Google Scholar 

  16. Bertino EM, Confer PD, Colonna JE et al (2009) Pulmonary neuroendocrine/carcinoid tumors: a review article. Cancer 115:4434–4441

    Article  PubMed  Google Scholar 

  17. Moertel CG (1983) Treatment of the carcinoid tumor and the malignant carcinoid syndrome. J Clin Oncol 1:727–740

    CAS  PubMed  Google Scholar 

  18. Sun W, Lipsitz S, Catalano P et al (2005) Phase II/III Study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23:4897–4904

    Article  CAS  PubMed  Google Scholar 

  19. Dowell JE (2010) Small cell lung cancer: are we making progress? Am J Med Sci 339:68–76

    Article  PubMed  Google Scholar 

  20. Shah N, Dizon DS (2009) New-generation platinum agents for solid tumors. Future Oncol 5:33–42

    Article  CAS  PubMed  Google Scholar 

  21. Dhar S, Lippard SJ (2009) Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A 106:22199–22204

    Article  CAS  PubMed  Google Scholar 

  22. Chong CD, Logothetis CJ, Savaraj N et al (1988) The correlation of vinblastine pharmacokinetics to toxicity in testicular cancer patients. J Clin Pharmacol 28:714–718

    CAS  PubMed  Google Scholar 

  23. Rowinsky EK, Burke PJ, Karp JE et al (1989) Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res 49:4640–4647

    CAS  PubMed  Google Scholar 

  24. Dennis MJ, Beijnen JH, Grochow LB, van Warderdam LJC (1997) An overview of the clinical pharmacology of topotecan. Semin Oncol 24:12–18S

    Google Scholar 

  25. Ho DH, Pazdur R, Covington W et al (1998) Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2′-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 4:2085–2088

    CAS  PubMed  Google Scholar 

  26. Wihlm J, Limacher JM, Leveque D et al (1997) Pharmacokinetic profile of high-dose doxorubicin administered during a 6 h intravenous infusion in breast cancer patients. Bull Cancer 84:603–608

    CAS  PubMed  Google Scholar 

  27. Touroutoglou N, Gravel D, Raber MN et al (1998) Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 9:1003–1008

    Article  CAS  PubMed  Google Scholar 

  28. Kivisto KT, Villikka K, Nyman L et al (1998) Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampicin. Clin Pharmacol Ther 64:648–654

    Article  CAS  PubMed  Google Scholar 

  29. Bonetti A, Franceschi T, Apostoli P et al (1995) Cisplatin pharmacokinetics using a five-day schedule during repeated courses of chemotherapy in germ cell tumors. Ther Drug Monit 17:25–32

    Article  CAS  PubMed  Google Scholar 

  30. Graham MA, Lockwood GF, Greenslade D et al (2000) Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 6:1205–1218

    CAS  PubMed  Google Scholar 

  31. Oguri S, Sakakibara T, Mase H et al (1988) Clinical pharmacokinetics of carboplatin. J Clin Pharmacol 28:208–215

    CAS  PubMed  Google Scholar 

  32. Schilcher RB, Young JD, Ratanatharathorn V et al (1984) Clinical pharmacokinetics of highdose mitomycin C. Cancer Chemother Pharmacol 13:186–190

    Article  CAS  PubMed  Google Scholar 

  33. Adolphe AB, Glasofer ED, Troetel WM et al (1975) Fate of streptozotocin (NSC-85998) in patients with advanced cancer. Cancer Chemother Rep 9:547–556

    Google Scholar 

  34. Hande K, Messenger M, Wagner J et al (1999) Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug application. Clin Cancer Res 5:2742–2747

    CAS  PubMed  Google Scholar 

  35. Chabot GG, Flaherty LE, Valdivieso M, Baker LH (1990) Alteration of DTIC pharmacokinetics after interleukin-2 administration in melanoma patients. Cancer Chemother Pharmacol 27:157–160

    Article  CAS  PubMed  Google Scholar 

  36. Kvols LK, Moertel CG, O’Connell MJ et al (1986) Treatment of the malignant carcinoid evaluation of a long-acting somatostatin analog. N Engl J Med 315:663–666

    Article  CAS  PubMed  Google Scholar 

  37. Engstrom PF, Lavin PT, Moertel CG et al (1984) Streptozotocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 8:865–890

    Google Scholar 

  38. Vilar E, Salazar R, Pérez-García J et al (2007) Chemotherapy and role of the proliferation marker Ki-67 in digestive neuroendocrine tumors. Endocr Relat Cancer 14:221–23

    Article  CAS  PubMed  Google Scholar 

  39. García-Yuste M, Matilla JM, Cueto A et al (2007) Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung. Eur J Cardiothorac Surg 31:192–197

    Article  PubMed  Google Scholar 

  40. Giaccone G, Battey J, Gazdar AF et al (1992) Neuromedin B is present in lung cancer cell lines. Cancer Res 52:2732s–2736s

    CAS  PubMed  Google Scholar 

  41. Saltz L, Lauwers G, Wiseberg J, Kelsen D (1993) A phase II trial of carboplatin in patients with advanced APUD tumors. Cancer 72:619–622

    Article  CAS  PubMed  Google Scholar 

  42. Skov BG, Holm B, Erreboe A et al (2010) ERCC1 and Ki67 in small cell lung carcinoma and other neuroendocrine tumors of the lung: distribution and impact on survival. J Thorac Oncol 5:453–459

    Article  PubMed  Google Scholar 

  43. Kelly K (2000) New chemotherapy agents for small cell lung cancer. Chest 117:156–162S

    Article  Google Scholar 

  44. Teicher BA (2008) Newer cytotoxic agents: attacking cancer broadly. Clin Cancer Res 14:1610–1617

    Article  CAS  PubMed  Google Scholar 

  45. Ansell SM, Pitot HC, Burch PA et al (2001) A phase II study of high-dose paclitaxel in patients with advanced neuroendocrine tumors. Cancer 91:1543–1548

    Article  CAS  PubMed  Google Scholar 

  46. Iyer L, Ratain MJ (1998) Clinical pharmacology of camptothecins. Cancer Chemother Pharmacol 42:S31–S43

    Article  CAS  PubMed  Google Scholar 

  47. Catimel G, Chabot GG, Guastalla JP et al (1995) Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors. Ann Oncol 6:133–140

    CAS  PubMed  Google Scholar 

  48. Lyons JM 3rd, Abergel J, Thomson JL et al (2009) In vitro chemoresistance testing in well-differentiated carcinoid tumors. Ann Surg Oncol 16:649–655

    Article  PubMed  Google Scholar 

  49. Porter AT, Ostrowski MJ (1988) Successful treatment of malignant carcinoid tumour with intravenous cisplatinum. Eur J Surg Oncol 14:703–704

    CAS  PubMed  Google Scholar 

  50. Olszewski U, Hamilton G (2010) A better platinum-based anticancer drug yet to come? Anticancer Agents Med Chem 10:293–301

    CAS  PubMed  Google Scholar 

  51. Wasilewski M, Scorrano L (2009) The changing shape of mitochondrial apoptosis. Trends Endocrinol Metab 20:287–294

    Article  CAS  PubMed  Google Scholar 

  52. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolictargeting therapy for cancer. Br J Cancer 99:989–994

    Article  CAS  PubMed  Google Scholar 

  53. Sun RC, Fadia M, Dahlstrom JE et al (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260

    Article  CAS  PubMed  Google Scholar 

  54. Otterson GA, Wang L, Wu X et al (2008) Effect of dichloroacetate in combination with chemotherapy on human lung cancer cells. J Clin Oncol 26S:14637

    Google Scholar 

  55. Dhar S, Lippard SJ (2009) Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A 106:22199–22204

    Article  CAS  PubMed  Google Scholar 

  56. Li T, Schultz I, Keys DA et al (2008) Quantitative evaluation of dichloroacetic acid kinetics in human: a physiologically based pharmacokinetic modeling investigation. Toxicology 245: 35–48

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine I Division of Oncology, St. Poelten Hospital, St. Poelten, Austria

    Wolfgang Fiebiger

  2. Ludwig Boltzmann Cluster of Translational Oncology, C/o Balderichgasse, 26/13, 1170, Vienna, Austria

    Ulrike Olszewski, Ernst Ulsperger, Klaus Geissler & Gerhard Hamilton

  3. Department of Surgery, Medical University Vienna, Vienna, Austria

    Gerhard Hamilton

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  1. Wolfgang Fiebiger
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  2. Ulrike Olszewski
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  4. Klaus Geissler
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  5. Gerhard Hamilton
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Correspondence to Gerhard Hamilton.

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Fiebiger, W., Olszewski, U., Ulsperger, E. et al. In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. Clin Transl Oncol 13, 43–49 (2011). https://doi.org/10.1007/s12094-011-0615-z

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  • DOI: https://doi.org/10.1007/s12094-011-0615-z

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