Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
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Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2010, vol. 19, nr 1, January-February, p. 5–12

Publication type: editorial article

Language: English

Mechanisms of Resistance to Cancer Chemotherapy

Mechanizmy oporności w chemioterapii nowotworów

Ewa Stefanko1,, Tomasz Wróbel1,

1 Department of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Poland


Resistance to chemotherapy is one of the major causes of failure of anticancer treatment. It can occur at every level of the drug action and includes mechanisms such as increased drug efflux and decreased influx, drug inactivation, alterations in the drug target, DNA damage repair, and evasion of apoptosis. In this article some mechanisms of drug resistance in cancer chemotherapy are reviewed.


Oporność na chemioterapię jest jedną z głównych przyczyn niepowodzeń leczenia przeciwnowotworowego. Zjawisko to może pojawić się na każdym poziomie działania leku i obejmuje takie mechanizmy, jak: zmniejszony pobór leku przez komórkę lub jego zwiększone usuwanie, inaktywację leku, zmniejszenie lub zwiększenie stężenia/ /aktywności miejsca docelowego działania leku, naprawa uszkodzonego przez cytostatyki DNA oraz zmiany w regulacji apoptozy. W artykule omówiono niektóre mechanizmy oporności na cytostatyki w komórkach nowotworowych.

Key words

resistance to chemotherapy, cancer cells, leukemia, lymphomas

Słowa kluczowe

oporność na chemioterapię, komórki nowotworowe, białaczka, chłoniaki

References (40)

  1. Assaraf YG: Molecular basis of antifolate resistance. Cancer Metastasis Rev 2007 Mar, 26, 153–181.
  2. Leverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M: Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002, 100, 3832–3834.
  3. Clark RE, Davies A, Pirmohamed M, Giannoudis A: Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. Leuk Lymphoma. 2008, 49, 639–642.
  4. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, Zannettino A, Lynch K, Manley PW, Hughes T: Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007, 110, 4064–4072.
  5. Shnitsar V, Eckardt R, Gupta S, Grottker J, Müller GA, Koepsell H, Burckhardt G, Hagos Y: Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine. Cancer Res 2009, 69, 1494–1501.
  6. Szendrei T, Magyarlaki T, Kovács G, Nagy A, Szomor A, Molnár L, Dávid M, Tokés-Füzesi M, Rideg O, Pótó L, Pajor L, Kajtár B, Losonczy H: Multidrug resistance in chronic lymphocytic leukemia. Orv Hetil 2008, 149, 161–167.
  7. Guillaume N, Gouilleux-Gruart V, Claisse JF, Troussard X, Lepelley P, Damaj G, Royer B, Garidi R, Lefrere JJ: Multi-drug resistance mediated by P-glycoprotein overexpression is not correlated with ZAP-70/CD38 expression in B-cell chronic lymphocytic leukemia. Leuk Lymphoma 2007, 48, 1468–1469.
  8. Ho MM, Hogge DE, Ling V: MDR1 and BCRP1 expression in leukemic progenitors correlates with chemotherapy response in acute myeloid leukemia. Exp Hematol 2008, 36, 433–442.
  9. Kourti M, Vavatsi N, Gombakis N, Sidi V, Tzimagiorgis G, Papageorgiou T, Koliouskas D, Athanassiadou F: Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol 2007, 86, 166–173.
  10. Wang D, Ke XY, Wang J, Wang J, Xu F, Hu YF: Correlation between MDR1 genetic polymorphism and prognosis in acute myeloid leukemia. Zhonghua Yi Xue Za Zhi 2007, 87, 1384–1388.
  11. Yang Z, Wu D, Bui T, Ho RJ: A novel human multidrug resistance gene MDR1 variant G571A (G191R) modulates cancer drug resistance and efflux transport. J Pharmacol Exp Ther 2008, 327, 474–481.
  12. Mahjoubi F, Golalipour M, Ghavamzadeh A, Alimoghaddam K: Expression of MRP1 gene in acute leukemia. Sao Paulo Med J 2008, 126, 172–179.
  13. Podolak-Dawidziak M, Duś D, Kiełbiński M, Paprocka M, Wojdat E, Lenart K, Szyda A, Haus O, Kuliszkiewicz-Janus M, Duszeńko E, Prajs I, Kuliczkowski K: Clinical relevance of multidrug resistance proteins expression in patients with de novo acute myeloid leukaemia. Adv Clin Exp Med 2005, 14, 1151–1160.
  14. Candoni A, Michelutti A, Simeone E, Damiani D, Baccarani M, Fanin R: Efficacy of liposomal daunorubicin and cytarabine as reinduction chemotherapy in relapsed acute lymphoblastic leukaemia despite expression of multidrug resistance-related proteins. Eur J Haematol 2006, 77, 293–299.
  15. Huang BT, Xiao Z, Shi YT, Ha S, Zhao WH, Gao D, Yan XH, Yang H: Expressions of LRP, GST-pi and MRP1 in acute leukemia patients and its clinical significance. J Exp Hematol 2007, 15, 262–266.
  16. Wróbel T, Mazur G, Dzięgiel P, Surowiak P, Kuliczkowski K, Zabel M: Expression of metallothionein (MT) and gluthatione s-transferase pi (SGTP) in the bone marrow of patients with myeloproliferative disorders (MPD). Folia Morphol 2004, 63, 129–131.
  17. Bennaceur-Griscelli A, Bosq J, Kościelny S, Lefrère F, Turhan A, Brousse N, Hermine O, Ribrag V: High level of glutathione-S-transferase pi expression in mantle cell lymphomas. Clin Cancer Res 2004, 10, 3029–3034.
  18. Asano T, Tsutsuda-Asano A, Fukunaga Y: Indomethacin overcomes doxorubicin resistance by decreasing intracellular content of glutathione and its conjugates with decreasing expression of gamma-glutamylcysteine synthetase via promoter activity in doxorubicin-resistant leukemia cells. Cancer Chemother Pharmacol 2009, 64, 715–721.
  19. Ouyang Z, Du QF, Liu XL, Zhang S, Zhu HQ, Gong JM, Song LL, Ouyang LY, Liu Z: Detection of ABL kinase domain point mutations in chronic myeloid leukemia patients receiving imatinib treatment. Nan Fang Yi Ke Da Xue Xue Bao 2008, 28, 704–706.
  20. Goker E, Waltham M, Kheradpour A, Trippett T, Mazumdar M, Elisseyeff Y, Schnieders B, Steinherz P, Tan C, Berman E: Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations. Blood 1995, 86, 677–684.
  21. Kavallaris M, Tait AS, Walsh BJ, He L, Horwitz SB, Norris MD, Haber M: Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells. Cancer Res 2001, 61, 5803–5809.
  22. Gan PP, Kavallaris M: Tubulin-targeted drug action: functional significance of class II and class IVb beta-tubulin in vinca alkaloid sensitivity. Cancer Res 2008, 68, 9817–9824.
  23. Mao G, Yuan F, Absher K, Jennings CD, Howard DS, Jordan CT, Gu L: Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression. Cell Res 2008, 18, 281–289.
  24. Miyashita K, Fujii K, Yamada Y, Hattori H, Taguchi K, Yamanaka T, Yoshida MA, Okamura J, Oda S, Muta K, Nawata H, Takayanagi R, Uike N: Frequent microsatellite in non-Hodgkin lymphomas irresponsive to chemotherapy. Leuk Res 2008, 32, 1183–1195.
  25. Velangi MR, Matheson EC, Morgan GJ, Jackson GH, Taylor PR, Hall AG, Irving JA: DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma. Carcinogenesis 2004, 25, 1795–1803.
  26. Lin X, Howell SB: DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance. Mol Cancer Ther 2006, 5, 1239–1247.
  27. Bendardaf R, Lamlum H, Ristamäki R, Korkeila E, Syrjänen K, Pyrhönen S: Mismatch repair status is a predictive factor of tumour response to 5-fluorouracil and irinotecan chemotherapy in patients with advanced colorectal cancer. Tumour Biol 2007, 28, 212–220.
  28. Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U, Fink D: Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int J Cancer 2001, 93, 571–576.
  29. Barret JM, Calsou P, Salles B: Deficient nucleotide excision repair activity in protein extracts from normal human lymphocytes. Carcinogenesis 1995, 16, 1611–1616.
  30. Shimizu J, Horio Y, Osada H, Hida T, Hasegawa Y, Shimokata K, Takahashi T, Sekido Y, Yatabe Y: mRNA expression of MMR1, ERCC1 and ERCC2 is not associated with chemosensitivity to cisplatin, carboplatin and gemcitabine in human lung cancer cell lines. Resiprology 2008, 13, 510–517.
  31. Azim HA Jr, Pruneri G, Raviele PR, Steffanoni S, Martinelli G, Peccatori FA: ERCC1 Expression in Diffuse Large B-Cell Lymphoma Patients Treated with a Cisplatin-Based Regimen: A Brief Communication. J Egypt Natl Canc Inst 2007, 19, 176–177.
  32. Aqarwal B, Naresh KN: Bcl-2 family of proteins in indolent B-cell non-Hodgkin’s lymphoma; study of 116 cases. Am J Hematol 2002, 70, 278–282.
  33. Del Poeta G, Bruno A, Del Principe MI, Venditti A, Maurillo L, Buccisano F, Stasi R, Neri B, Luciano F, Siniscalchi A, de Fabritiis P, Amadori S: Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. Curr Cancer Drug Targets 2008, 8, 207–222.
  34. Mazur G, Haloń A, Wróbel T, Urbaniak J, Kuliczkowski K, Woźniak M: Survivin expression in lymph nodes, affected by lymphoma and reactive hyperplasia. Rocz Akad Med Bialymst. 2004, 49 Suppl 1, 76–78.
  35. Adida C, Haioun C, Gaulard P, Lepage E, Morel P, Briere J, Dombret H, Reyes F, Diebold J, Gisselbrecht C, Salles G, Altieri DC, Molina TJ: Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 2000, 96, 1921–1925.
  36. Troeger A, Siepermann M, Escherich G, Meisel R, Willers R, Gudowius S, Moritz T, Laws HJ, Hanenberg H, Goebel U, Janka-Schaub GE, Mahotka C, Dilloo D: Survivin and its prognostic significance in pediatric acute B-cell precursor lymphoblastic leukemia. Haematologica 2007, 92, 1043–1050.
  37. Yamamoto K, Abe S, Nakagawa Y, Suzuki K, Hasegawa M, Inoue M, Kurata M, Hirokawa K, Kitagawa M: Expression of IAP family proteins in myelodysplastic syndrome transforming to overt leukemia. Leuk Res 2004, 28, 1203–1211.
  38. Li J, Lee AS: Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med. 2006, 6, 45–54.
  39. Jiang CC, Mao ZG, Avery-Kiejda KA, Wade M, Hersey P, Zhang XD: Glucose-regulated protein 78 antagonizes cisplatin and adriamycin in human melanoma cells. Carcinogenesis 2009, 30, 197–204.
  40. Daneshmand S, Quek ML, Lin E, Lee C, Cote RJ, Hawes D, Cai J, Groshen S, Lieskovsky G, Skinner DG, Lee AS, Pinski J: Glucose-regulated protein GRP78 is up-regulated in prostate cancer and correlates with recurrence and survival. Hum Pathol 2007, 38, 1547–1552.