Does MDR1 promoter methylation affect temozolomide resistance? A clinical study in patients with glioblastoma
Abstract
Purpose: The multidrug resistance 1 (MDR1) gene expression and its epigenetic status may be an important factor in the chemotherapeutic resistance of glioblastoma (GB). The aim of this study was to analyze the effect of the MDR1 promoter methylation status on GB tumor tissue related with patient survival, chemotherapy resistance, and recurrence of the disease.
Materials and methods: Thirty-six patients underwent surgery for GB at the Neurosurgery Department of Ankara University School of Medicine. The patients’ clinical information and the MDR1 methylation status of the tumor tissues was compared to determine the effects on patient survival, chemotherapy resistance, and tumor recurrence.
Results: Patients with MDR1 methylated GB had statistically significantly (p<0.001) shorter survival times. Early recurrence was detected in 25% of the patients with unmethylated tumor tissues and in 39.3% with hemimethylated tumor tissues.
Conclusion: Instead of using the standard chemotherapeutics in all the patients with GB, tissue-specific medications must be chosen while taking into consideration the epigenomic characteristics and expression status of the tumor because of the genetic heterogeneity of GB. This is the first study to show the association between MDR1 promoter methylation and the clinical data of GB in the literature.
Supporting Institution
Yok
Project Number
Yok
Thanks
This study was partially presented as a poster at the Personalized Medicine Conference set for May 18-20, 2016 in Tübingen, Germany
References
- 1. Krakstad C, Chekenya M. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer. 2010;9:135.
- 2. Adamson C, Kanu OO, Mehta AI, et al. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009;Aug;18(8):1061-83.
- 3. Rosell R, de Las Peñas R, Balaña C, et al. Translational research in glioblastoma multiforme: molecular criteria for patient selection. Future Oncol. 2008;Apr;4(2):219-28.
- 4. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137-71.
- 5. Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science Sep. 1983; 23;221(4617):1285-8.
- 6. Feun LG, Savaraj N, Landy HJ. Drug resistance in brain tumors. J Neurooncol. 1994;20(2):165-76.
- 7. Schaich M, Kestel L, Pfirrmann M, et al. A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 2009;Jan;20(1):175-81.
- 8. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;Nov 10;31(32):4085-91.
- 9. Khasraw M, Lassman AB. Advances in the treatment of malignant gliomas. Curr Oncol Rep. 2010; Jan;12(1):26-33.
- 10. Tahara T, Shibata T, Yamashita H, et al. Promoter methylation status of multidrug resistance 1 (MDR1) gene in noncancerous gastric mucosa correlates with Helicobacter Pylori infection and gastric cancer occurrence. Cancer Invest. 2010;Aug;28(7):711-6.
- 11. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;Oct 20;22(47):7468-85.
- 12. Chen CJ, Clark D, Ueda K, Pastan I, Gottesman MM, Roninson IB. Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem. 1990;Jan 5;265(1):506-14.
- 13. Takanishi K, Miyazaki M, Ohtsuka M, Nakajima N. Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma. Oncology. 1997;May-Jun;54(3):231-7.
- 14. Scotlandi K, Manara MC, Serra M, et al. The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells. Oncogene. 1999;Jan 21;18(3):739-46.
- 15. Goldstein LJ, Galski H, Fojo A, et al. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst. 1989;Jan 18;81(2):116-24.
- 16. Pastan I, Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med. 1987;May 28;316(22):1388-93.
- 17. Matsumoto T, Tani E, Kaba K, et al. Amplification and expression of a multidrug resistance gene in human glioma cell lines. J Neurosurg. 1990;Jan;72(1):96-101.
- 18. Podolski-Renić A, Jadranin M, Stanković T, et al. Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing. Cancer Chemother Pharmacol. 2013;Sep;72(3):683-97.
- 19. Qiu YY, Mirkin BL, Dwivedi RS. MDR1 hypermethylation contributes to the progression of neuroblastoma. Mol Cell Biochem. 2007;Jul;301(1-2):131-5.
- 20. Yegnasubramanian S, Kowalski J, Gonzalgo ML, et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res. 2004;Mar 15;64(6):1975-86.
- 21. Bastian PJ, Palapattu GS, Yegnasubramanian S, et al. CpG island hypermethylation profile in the serum of men with clinically localized and hormone refractory metastatic prostate cancer. J Urol. 2008;Feb;179(2):529-34; discussion 534-5.
- 22. Ellinger J, Bastian PJ, Jurgan T, et al. CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer. Urology. 2008;Jan;71(1):161-7.
- 23. von Bossanyi P, Diete S, Dietzmann K, Warich-Kirches M, Kirches E. Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy. Acta Neuropathol. 1997;Dec;94(6):605-11.
- 24. Yokogami K, Kawano H, Moriyama T, et al. Application of SPET using technetium-99m sestamibi in brain tumours and comparison with expression of the MDR-1 gene: is it possible to predict the response to chemotherapy in patients with gliomas by means of 99mTc-sestamibi SPET? Eur J Nucl Med. 1998;Apr;25(4):401-9.
- 25. Abe T, Mori T, Wakabayashi Y, et al. Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. J Neurooncol. 1998;Oct;40(1):11-8.
Abstract
Amaç: Çoklu ilaç direnci 1 (MDR1) gen ekspresyonu ve epigenetik durumu, glioblastomun (GB) kemoterapötik direncinde önemli bir faktör olabilir. Bu çalışmanın amacı, MDR1 promoter metilasyon durumunun, hastanın sağkalımı, kemoterapi direnci ve hastalığın tekrarlaması ile ilgili olarak GB tümör dokusu üzerindeki etkisini analiz etmektir.
Gereç ve yöntem: …. Üniversitesi Tıp Fakültesi Beyin Cerrahisi Anabilim Dalı'nda GB tanısı ile ameliyat edilen 36 hastanın verileri incelendi. Hastaların klinik bilgileri ve tümör dokularının MDR1 metilasyon durumu, hastanın sağkalımı, kemoterapi direnci ve tümör nüksü üzerindeki etkilerine yönelik karşılaştırıldı.
Bulgular: MDR1’nin metile olduğu GB'li hastalarda istatistiksel olarak anlamlı (p<0,001) daha kısa sağkalım süreleri saptandı. Metile tümör dokusu olan hastaların %25'inde ve hemi-metile tümör dokusu olan hastaların %39,3'ünde erken rekürrens saptandı.
Sonuç: GB'li tüm hastalarda standart kemoterapötikleri kullanmak yerine, GB'nin genetik heterojenliği nedeniyle tümörün epigenomik özellikleri ve ekspresyon durumu dikkate alınarak dokuya özgü ilaçlar seçilmelidir. Bu, literatürdeki MDR1 promoter metilasyonu ile GB'nin klinik verileri arasındaki ilişkiyi gösteren ilk çalışmadır.
Project Number
Yok
References
- 1. Krakstad C, Chekenya M. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer. 2010;9:135.
- 2. Adamson C, Kanu OO, Mehta AI, et al. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009;Aug;18(8):1061-83.
- 3. Rosell R, de Las Peñas R, Balaña C, et al. Translational research in glioblastoma multiforme: molecular criteria for patient selection. Future Oncol. 2008;Apr;4(2):219-28.
- 4. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137-71.
- 5. Kartner N, Riordan JR, Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science Sep. 1983; 23;221(4617):1285-8.
- 6. Feun LG, Savaraj N, Landy HJ. Drug resistance in brain tumors. J Neurooncol. 1994;20(2):165-76.
- 7. Schaich M, Kestel L, Pfirrmann M, et al. A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol 2009;Jan;20(1):175-81.
- 8. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;Nov 10;31(32):4085-91.
- 9. Khasraw M, Lassman AB. Advances in the treatment of malignant gliomas. Curr Oncol Rep. 2010; Jan;12(1):26-33.
- 10. Tahara T, Shibata T, Yamashita H, et al. Promoter methylation status of multidrug resistance 1 (MDR1) gene in noncancerous gastric mucosa correlates with Helicobacter Pylori infection and gastric cancer occurrence. Cancer Invest. 2010;Aug;28(7):711-6.
- 11. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;Oct 20;22(47):7468-85.
- 12. Chen CJ, Clark D, Ueda K, Pastan I, Gottesman MM, Roninson IB. Genomic organization of the human multidrug resistance (MDR1) gene and origin of P-glycoproteins. J Biol Chem. 1990;Jan 5;265(1):506-14.
- 13. Takanishi K, Miyazaki M, Ohtsuka M, Nakajima N. Inverse relationship between P-glycoprotein expression and its proliferative activity in hepatocellular carcinoma. Oncology. 1997;May-Jun;54(3):231-7.
- 14. Scotlandi K, Manara MC, Serra M, et al. The expression of P-glycoprotein is causally related to a less aggressive phenotype in human osteosarcoma cells. Oncogene. 1999;Jan 21;18(3):739-46.
- 15. Goldstein LJ, Galski H, Fojo A, et al. Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst. 1989;Jan 18;81(2):116-24.
- 16. Pastan I, Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med. 1987;May 28;316(22):1388-93.
- 17. Matsumoto T, Tani E, Kaba K, et al. Amplification and expression of a multidrug resistance gene in human glioma cell lines. J Neurosurg. 1990;Jan;72(1):96-101.
- 18. Podolski-Renić A, Jadranin M, Stanković T, et al. Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing. Cancer Chemother Pharmacol. 2013;Sep;72(3):683-97.
- 19. Qiu YY, Mirkin BL, Dwivedi RS. MDR1 hypermethylation contributes to the progression of neuroblastoma. Mol Cell Biochem. 2007;Jul;301(1-2):131-5.
- 20. Yegnasubramanian S, Kowalski J, Gonzalgo ML, et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res. 2004;Mar 15;64(6):1975-86.
- 21. Bastian PJ, Palapattu GS, Yegnasubramanian S, et al. CpG island hypermethylation profile in the serum of men with clinically localized and hormone refractory metastatic prostate cancer. J Urol. 2008;Feb;179(2):529-34; discussion 534-5.
- 22. Ellinger J, Bastian PJ, Jurgan T, et al. CpG island hypermethylation at multiple gene sites in diagnosis and prognosis of prostate cancer. Urology. 2008;Jan;71(1):161-7.
- 23. von Bossanyi P, Diete S, Dietzmann K, Warich-Kirches M, Kirches E. Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy. Acta Neuropathol. 1997;Dec;94(6):605-11.
- 24. Yokogami K, Kawano H, Moriyama T, et al. Application of SPET using technetium-99m sestamibi in brain tumours and comparison with expression of the MDR-1 gene: is it possible to predict the response to chemotherapy in patients with gliomas by means of 99mTc-sestamibi SPET? Eur J Nucl Med. 1998;Apr;25(4):401-9.
- 25. Abe T, Mori T, Wakabayashi Y, et al. Expression of multidrug resistance protein gene in patients with glioma after chemotherapy. J Neurooncol. 1998;Oct;40(1):11-8.
Details
| Primary Language | English |
|---|---|
| Subjects | Surgery |
| Journal Section | Research Article |
| Authors | |
| Project Number | Yok |
| Publication Date | July 1, 2022 |
| Submission Date | December 23, 2021 |
| Acceptance Date | February 21, 2022 |
| Published in Issue | Year 2022 Volume: 15 Issue: 3 |
Cite
