THE EFFECT OF MULTIDRUG RESISTANCE GENE EXPRESSION ON THE CLINICAL COURSE OF MULTIPLE MYELOMA

Cover Page


Cite item

Full Text

Abstract

Background: Implementation of a proteasome inhibitor bortezomib into treatment of multiple myeloma has helped to improve survival of patients with this malignancy that is characterized by continuous relapsing course as a clinical manifestation of multidrug resistance (MDR). Previous studies have resulted in contradictory data on the effects of various MDR genes expression on efficacy of bortezomib. Aim: To evaluate an impact of MDR1, MRP1, LRP, BCRP gene mRNA expression responsible for the development of MDR in bone marrow aspirates from patients with newly diagnosed multiple myeloma before bortezomib-containing therapy on the clinical course of the disease, response to treatment and overall survival. Materials and methods: MDR gene expression was assessed in a  group of 15  patients with newly diagnosed multiple myeloma Durie-Salmon stage  III before initiation of a bortezomib-based chemotherapeutic regimen. The assessment was done in bone marrow mononuclear cell fraction containing plasmocytes. MDR gene expression was measured by reverse transcription polymerase chain reaction test. Results: MDR gene expression was found in all patients with newly diagnosed multiple myeloma before initiation of cytostatic therapy: MDR1 was expressed in 14 (93%) of patients, MRP1 and LRP  – in 11 (73%), BCRP  – in 15  (100%). There was no difference between patient subgroups with high and low MDR gene expression in their clinical parameters, such as hemoglobin level, erythrocyte counts, total calcium, creatinine, total protein, lactate dehydrogenase, and albumin. At diagnosis of multiple myeloma, only absolute levels of paraprotein were significantly lower in patients with high MDR1 gene expression (31.52±3 vs  44.27±3.62  g/L, p<0.05). After 6  cycles of induction, there was a  significant decrease of paraprotein levels in the group with low MDR1 gene expression (from 44.3±3.6 to 16.8±5.2 g/L, p<0.05). Overall survival was negatively associated with high LRP gene expression only (median of overall survival in patients with high LRP gene expression was 17 months and in those with low expression – 62 months, р<0.05). Conclusion: High expression of MDR genes in patients with newly diagnosed multiple myeloma is not associated with clinical characteristics of the disease but may deteriorate the immediate response to bortezomib-based regimens and overall survival.

About the authors

Yu. B. Chernykh

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Author for correspondence.
Email: yulia_chernih@mail.ru
MD, Research Fellow, Department of Clinical Hematology and Immunotherapy Russian Federation

A. K. Golenkov

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Professor, Head of Department of Clinical Hematology and Immunotherapy Russian Federation

S. S. Shushanov

N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe shosse, Moscow, 115478, Russian Federation

Email: yulia_chernih@mail.ru
PhD, Doctor of Biol. Sci., Leading Research Fellow, Laboratory of Tumor Cells Genetics Russian Federation

T. A. Kravtsova

N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe shosse, Moscow, 115478, Russian Federation

Email: yulia_chernih@mail.ru
Junior Research Fellow, Laboratory of Tumor Cells Genetics Russian Federation

E. Yu. Rybalkina

N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe shosse, Moscow, 115478, Russian Federation

Email: yulia_chernih@mail.ru
PhD (in Biol.), Senior Research Fellow, Laboratory of Tumor Cells Genetics Russian Federation

A. F. Karamysheva

N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe shosse, Moscow, 115478, Russian Federation

Email: yulia_chernih@mail.ru
PhD, Doctor of Biol. Sci., Head of Laboratory of Tumor Cells Genetics Russian Federation

T. A. Mitina

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy Russian Federation

E. V. Trifonova

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy Russian Federation

E. V. Kataeva

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Senior Research Fellow, Department of Clinical Hematology and Immunotherapy Russian Federation

L. L. Vysotskaya

Moscow Regional Research and Clinical Institute (MONIKI); 61/2 Shchepkina ul., Moscow, 129110, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Research Fellow, Department of Clinical Hematology and Immunotherapy Russian Federation

A. A. Stavrovskaya

N.N. Blokhin Russian Cancer Research Center; 24 Kashirskoe shosse, Moscow, 115478, Russian Federation

Email: yulia_chernih@mail.ru
MD, PhD, Professor, Leading Research Fellow, Laboratory of Tumor Cells Genetics Russian Federation

References

  1. Волкова ТО, Багина УС. Множественная лекарственная устойчивость опухолевых клеток к химиотерапевтическим препаратам. Принципы экологии. 2012;1(2): 4–21. doi: 10.15393/j1.art.2012.921.
  2. Ставровская АА. Множественная лекарственная устойчивость, обусловленная активностью транспортных белков клетки: некоторые новые факты и перспективы исследований. Биологические мембраны. 2003;20(3): 196–205.
  3. Moitra K. Overcoming multidrug resistance in cancer stem cells. Biomed Res Int. 2015;2015:635745. doi: 10.1155/2015/635745.
  4. Benderra Z, Faussat AM, Sayada L, Perrot JY, Chaoui D, Marie JP, Legrand O. Breast cancer resistance protein and P-glycoprotein in 149 adult acute myeloid leukemias. Clin Cancer Res. 2004;10(23): 7896–902. doi: 10.1158/1078-0432.CCR-04-0795.
  5. Kawabata S, Oka M, Soda H, Shiozawa K, Nakatomi K, Tsurutani J, Nakamura Y, Doi S, Kitazaki T, Sugahara K, Yamada Y, Kamihira S, Kohno S. Expression and functional analyses of breast cancer resistance protein in lung cancer. Clin Cancer Res. 2003;9(8): 3052–7.
  6. Wang N, Chen L, Wei B, Zheng W. Expression of ABCG2 in human gastric carcinoma. The Chinese-German Journal of Clinical Oncology. 2010;9(3): 145–8. doi: 10.1007/s10330-010-0003-0.
  7. Schwarzenbach H. Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med Oncol. 2002;19(2): 87–104. doi: 10.1385/MO:19:2:87.
  8. Sonneveld P. Multidrug resistance in hematological malignancies. Journal of Internal Medicine. 2000;247(5): 521–34. doi: 10.1046/j.1365-2796.2000.00689.x.
  9. Mutlu P, Kiraz Y, Gündüz U, Baran Y. An update on molecular biology and drug resistance mechanisms of multiple myeloma. Crit Rev Oncol Hematol. 2015;96(3): 413–24. doi: 10.1016/j.critrevonc.2015.07.003.
  10. O'Connor R, Ooi MG, Meiller J, Jakubikova J, Klippel S, Delmore J, Richardson P, Ander-son K, Clynes M, Mitsiades CS, O'Gorman P. The interaction of bortezomib with multidrug transporters: implications for therapeutic applications in advanced multiple myeloma and other neoplasias. Cancer Chemother Pharma-col. 2013;71(5): 1357–68. doi: 10.1007/s00280-013-2136-7.
  11. Голенков АК, Митина ТА, Когарко ИН, Любимова НВ, Клинушкина ЕФ, Барышников АЮ. Фармакодинамическая характеристика эффективности Велкейда при резистентной и рецидивной множественной миеломе: определение свободных легких цепей иммуноглобулинов сыворотки крови. Терапевтический архив. 2009;81(7): 37–41.
  12. Abraham J, Salama NN, Azab AK. The role of P-glycoprotein in drug resistance in multiple myeloma. Leuk Lymphoma. 2015;56(1): 26–33. doi: 10.3109/10428194.2014.907890.
  13. Панищева ЛА, Какпакова ЕС, Рыбалкина ЕЮ, Ставровская АА. Влияние ингибитора протеасом бортезомиба на экспрессию и активность АВС транспортеров в опухолевых клетках. Биологические мембраны. 2010;27(2): 195–201.
  14. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3): 842–54. doi: 10.1002/1097-0142(197509)36:33.0.CO;2-U.
  15. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20(9): 1467–73. doi: 10.1038/ sj.leu.2404284.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2016 Chernykh Y.B., Golenkov A.K., Shushanov S.S., Kravtsova T.A., Rybalkina E.Y., Karamysheva A.F., Mitina T.A., Trifonova E.V., Kataeva E.V., Vysotskaya L.L., Stavrovskaya A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies