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Predicting Effectiveness of Imatinib Mesylate in Tumors Expressing Platelet-Derived Growth Factors (PDGF-AA, PDGF-BB), Stem Cell Factor Ligands and Their Respective Receptors (PDGFR-α, PDGFR-β, and c-kit)

Abstract

Introduction

This research aims to optimize and predict the effectiveness of imatinib mesylate (imatinib) in tumors expressing platelet-derived growth factors (PDGF-AA, BB), kit/stem cell factor (SCF) ligands and their respective receptors (PDGFR-α, PDGFR-β, and c-kit).

Material and Methods

Samples of normal primary human T cells were incubated with graded concentrations of 1–5 μM imatinib. The energy yield by imatinib doses in those samples was identified in H-thymidine proliferation assay as described before in earlier studies. Tumor models of human pancreatic adenocarcinoma L3.6pl (PDGFAA/PDGFR-α-positive and KIT-negative), human male gonad Leydig tumor cells MA10 (PDGF-AA/PDGFR-α- positive and KIT-positive), human small-cell lung cancer [H209 (KIT-positive), NCI-H526 (PDGFR β-positive and KIT-positive), and NCI-H82 (PDGFR β-positive and KIT-negative)], and human neuroblastoma SMS-KCNR (PDGF-BB/PDGFR-β-positive and KIT-positive) in athymic nude mice were used. The antitumor activity of different doses of imatinib in different regimens in those xenografts was predicted as described before in earlier studies.

Results

The energy yield by drug doses was perfectly logarithmic correlated (r = 1) with the drug dose. An efficient dose-energy model with perfect fit (R = 1) estimating the energy yield by imatinib doses has been established to administer the personalized dose. Predictions for the antitumor activity of imatinib in those xenografts using the dose-energy model and the histologic grade of the control animals were 100 % identical to those actually induced.

Conclusion

The effect of imatinib is transient and reversible, reduces tyrosine phosphorylation of tumor-derived PDGFR-α, PDGFR-β, and c-kit without affecting their levels of expression. A resumption of tumor growth nearly identical to the growth prior to therapy should be expected whenever the treatment is stopped. Tumors of PDGF-AA/PDGFR-α exhibit significant resistance to imatinib which requires administering imatinib three times a day, whereas resistance of tumors of PDGF-BB/PDGFR-β or KIT-positive is relatively lower which requires administering imatinib two times a day only to produce an actual inhibition 100 % identical to that predicted for tumor growth.

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References

  1. Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med. 1996;74(10):589–607.

    CAS  PubMed  Article  Google Scholar 

  2. Crespo O, Kang SC, Daneman R, Lindstrom TM, Ho PP, Sobel RA, et al. Tyrosine kinase inhibitors ameliorate autoimmune encephalomyelitis in a mouse model of multiple sclerosis. J Clin Immunol. 2011. doi:10.1007/s10875-011-9579-6.

    PubMed Central  PubMed  Google Scholar 

  3. Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, Higgins JP, et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006;116:2633–42.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  4. Moawad EY. Induction of Multiple Sclerosis and Response to Tyrosine Kinase Inhibitors. Ind J Clin Biochem. 2014;29(4):491–5.

    CAS  Article  Google Scholar 

  5. Emad Y. Moawad (2013). Induction of rheumatoid arthritis and response to tyrosine kinase inhibitors. Universal Journal of Medical Science, 1 , 50–55. doi: 10.13189/ujmsj.2013.010205. http://www.hrpub.org/journals/article_info.php?aid=416

  6. Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000;295:139–45.

    CAS  PubMed  Google Scholar 

  7. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.

    CAS  PubMed  Google Scholar 

  8. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100–4.

    CAS  PubMed  Google Scholar 

  9. Okuda K, Weisberg E, Gilliland DG, Griffin JD. ARG tyrosine kinase activity is inhibited by STI571. Blood. 2001;97:2440–8.

    CAS  PubMed  Article  Google Scholar 

  10. Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 2002;20:1692–703.

    CAS  PubMed  Article  Google Scholar 

  11. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–52.

    CAS  PubMed  Article  Google Scholar 

  12. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

    PubMed  Article  Google Scholar 

  13. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001;344:1052–6.

    CAS  PubMed  Article  Google Scholar 

  14. DeMatteo RP. The GIST of targeted cancer therapy: a tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (STI571). Ann Surg Oncol. 2002;9:831–9.

    PubMed  Article  Google Scholar 

  15. Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood. 2004;104(7):2204–5.

    CAS  PubMed  Article  Google Scholar 

  16. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002;1:493–502.

    CAS  PubMed  Article  Google Scholar 

  17. Beppu K, Jaboine J, Merchant MS, Mackall CL, Thiele CJ. Effect of imatinib mesylate on neuroblastoma tumorigenesis and vascular endothelial growth factor expression. J Natl Cancer Inst. 2004;96:46–55.

    CAS  PubMed  Article  Google Scholar 

  18. Merchant MS, Woo CW, Mackall CL, Thiele CJ. Potential use of imatinib in Ewing’s Sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst. 2002;94:1673–9.

    CAS  PubMed  Article  Google Scholar 

  19. Krystal GW, Honsawek S, Litz J, Buchdunger E. The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth. Clin Cancer Res. 2000;6:3319–26.

    CAS  PubMed  Google Scholar 

  20. Moawad E. Isolated system towards a successful radiotherapy treatment. Nucl Med Mol Imaging. 2010;44:123–36. Free PMC Article.

    PubMed Central  PubMed  Article  Google Scholar 

  21. Moawad EY. Radiotherapy and risks of tumor regrowth or inducing second cancer. Cancer Nanotechnol. 2011;2:81–93.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. Emad Y. Moawad (2013). Safe doses and cancer treatment evaluation. Cancer and Oncology Research, 1 , 6–11. doi: 10.13189/cor.2013.010102. http://www.hrpub.org/journals/article_info.php?aid=48

  23. Emad Y. Moawad (2013). Pathologic cancer staging by measuring cell growth energy. Cancer and Oncology Research, 1 , 69–74. doi: 10.13189/cor.2013.010301. http://www.hrpub.org/journals/article_info.php?aid=660

  24. Emad Y. Moawad (2013). The mechanism by which chronic myeloid leukemia responds to interferon-α treatment. Advances in Pharmacology and Pharmacy, 1 , 88–94. doi: 10.13189/app.2013.010207. http://www.hrpub.org/journals/article_info.php?aid=451

  25. Moawad EY. Clinical and pathological staging of the cancer at the nanoscale. Cancer Nano. 2012;3:37–46.

    Article  Google Scholar 

  26. Moawad EY. Reconciliation between the clinical and pathological staging of cancer. Comp Clin Pathol. 2014;23:255–62.

    Article  Google Scholar 

  27. Moawad EY. Administering the optimum dose of L-arginine in regional tumor therapy. Ind J Clin Biochem. 2014;29(4):442–51.

    CAS  Article  Google Scholar 

  28. Moawad EY. Identifying the optimal dose of ritonavir in the treatment of malignancies. Metab Brain Dis. 2014;29:533–40.

    CAS  PubMed  Article  Google Scholar 

  29. Moawad EY. Optimal standard regimen and predicting response to docetaxel therapy. Mutat Res-Fundam Mol Mech Mutagen. 2014;770:120–7.

    CAS  Article  Google Scholar 

  30. Emad Y. Moawad (2013). Safe cancer screening for patients after lumpectomy, survivors, and healthy subjects. Cancer and Oncology Research, 1 , 15–23. doi: 10.13189/cor.2013.010201. http://www.hrpub.org/journals/article_info.php?aid=281

  31. Emad Y. Optimizing bioethanol production through regulating yeast growth energy. Syst Synth Biol. 2012;6:61–8. Free PMC Article.

    Article  Google Scholar 

  32. Emad Y. Moawad (2013). Growth energy of bacteria and the associated electricity generation in fuel cells. Bioengineering and Bioscience, 1 , 5–10. doi: 10.13189/bb.2013.01010 http://www.hrpub.org/journals/article_info.php?aid=129

  33. Emad Y. Moawad (2013). Nuclear transmutation and cancer in the biological cell. International Journal of Biochemistry and Biophysics, 1 , 1–8. doi: 10.13189/ijbb.2013.010101. http://www.hrpub.org/journals/article_info.php?aid=139

  34. Emad Y. Cell growth energy represents a measure for man health; regulates nuclear transmutations and aberrant activation in human cell. Univ J Med Sci. 2013;1:27–35. doi:10.13189/ujmsj.2013.010203. http://www.hrpub.org/journals/article_info.php?aid=414.

    Google Scholar 

  35. Emad Y. Moawad (2013). Purification of sewage water through the protection of the environment from radioactive contamination. Energy and Environmental Engineering, 1 , 55–61. doi: 10.13189/eee.2013.010203. http://www.hrpub.org/journals/article_info.php?aid=304

  36. Moawad, E. Y. (2015). Mass-energy conversion in the decaying system and doubling time-energy conversion in the biological system. Journal of Physics Research and Reviews, 1(1), 1–13. http://chromejournals.com/sci/index.php/JPRR/article/view/5

  37. Kyprianou N, English HF, Davidson NE, Isaacs JT. Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. Cancer Res. 1991;51(1):162–6.

    CAS  PubMed  Google Scholar 

  38. Steel GG. Growth kinetics of tumours. Cell population kinetics in relation to the growth and treatment of cancer. Oxford: Clarendon Press; 1977.

    Google Scholar 

  39. Dietz AB et al. Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood. 2004;104:1094–9.

    CAS  PubMed  Article  Google Scholar 

  40. Hwang RF, Yokoi K, Bucana CD, Tsan R, Killion JJ, Evans DB, et al. Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res. 2003;9(17):6534–44.

    CAS  PubMed  Google Scholar 

  41. Basciani S, Brama M, Mariani S, De Luca G, Arizzi M, Vesci L, et al. Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity. Cancer Res. 2005;65(5):1897–903.

    CAS  PubMed  Article  Google Scholar 

  42. Wolff NC, Randle DE, Egorin MJ, Minna JD, Ilaria RL. Imatinib mesylate efficiently achieves therapeutic intratumor concentrations in vivo but has limited activity in a xenograft model of small cell lung cancer. Clin Cancer Res. 2004;10(10):3528–34.

    CAS  PubMed  Article  Google Scholar 

  43. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor β in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2(5):471–8.

    CAS  PubMed  Article  Google Scholar 

  44. Kenneth Barbalace. Periodic Table of Elements - H - Hydrogen. EnvironmentalChemistry.com. 1995–2011. Accessed on-line: 12/21/2011http://EnvironmentalChemistry.com/yogi/periodic/H-pg2.html

  45. Zhang L, Yang N, Katsaros D, et al. The oncogene phosphatidylinositol 3 V-kinase catalytic subunit a promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res. 2003;63:4225–31.

    CAS  PubMed  Google Scholar 

  46. Emad Y. Moawad, Identifying and predicting the effectiveness of carboplatin in vivo and in vitro and evaluating its combination with paclitaxel. Indian J Gynecol Oncolog. 2015;13:1-9.

  47. Gambacorti-Passerini C, Barni R, le Coutre P, et al. Role of a1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571. J Natl Cancer Inst. 2000;92:1641–50.

    CAS  PubMed  Article  Google Scholar 

  48. Cohen PS, Chan JP, Lipkunskaya M, Biedler JL, Seeger RC. Expression of stem cell factor and c-kit in human neuroblastoma. Blood. 1994;84:3465–72.

    CAS  PubMed  Google Scholar 

  49. Timeus F, Crescenzio N, Valle P, Pistamiglio P, Piglione M, Garelli E, et al. Stem cell factor suppresses apoptosis in neuroblastoma cell lines. Exp Hematol. 1997;25:1253–60.

    CAS  PubMed  Google Scholar 

  50. Gschwind, Hans-Peter, Pfaar U, Waldmeier F, Zollinger M, Sayer C, et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos. 2005;33(10):1503–12.

    CAS  PubMed  Article  Google Scholar 

  51. Peng B, Dutreix C, Mehring G, Hayes MJ, Ben-Am M, Seiberling M, et al. Absolute bioavailability of imatinib (Glivec) orally versus intravenous infusion. J Clin Pharmacol. 2004;44:158–62.

    PubMed  Article  Google Scholar 

  52. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7. Free Full Text | Web of Science |.

    CAS  PubMed  Article  Google Scholar 

  53. Berman, Ellin, Nicolaides M, Maki RG, Fleisher M, Chanel S, et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med. 2006;354(19):2006–13.

    CAS  PubMed  Article  Google Scholar 

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The author declares that there is no conflict of interest concerning this paper.

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Correspondence to Emad Y. Moawad.

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Emad Y. Moawad is a member of the Korean Society of Nuclear Medicine

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Moawad, E.Y. Predicting Effectiveness of Imatinib Mesylate in Tumors Expressing Platelet-Derived Growth Factors (PDGF-AA, PDGF-BB), Stem Cell Factor Ligands and Their Respective Receptors (PDGFR-α, PDGFR-β, and c-kit). J Gastrointest Canc 46, 272–283 (2015). https://doi.org/10.1007/s12029-015-9721-4

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  • DOI: https://doi.org/10.1007/s12029-015-9721-4

Keywords

  • Imatinib
  • Dose-energy model
  • PDGF-AA, PDGF-BB
  • PDGFR-α, PDGFR-β
  • SCF/c-kit