The redox state of lymphocytes of patients (adults and children) with acute lymphoblastic leukemia (ALL) and their sensitivity was assessed before and after exposure to anticancer drugs (fludarabel, vincristine, dexamethasone, and imatinib) at concentrations close to therapeutic ones. It was found that alterations of reactive oxygen species level in leukemic cells after the short-term (2-3 h) and long-term (18-20 h) exposure to the studied drugs are differently directed. Affect of the investigated drugs on the children leukemic cells leads to an increase a cytosolic low molecular weight antioxidants (LMWA) content, but for donor’s cells this tendency is not observed. A fundamental difference of LMWA participation in the studied anticancer drugs metabolism in donor’s and patient’s cells was found. Moreover, cytosolic LMWA level in intact ALL children’s cells is an average 2 times higher than in donor’s cells. The individual sensitivity of the leukemic cells under anticancer drugs exposure is characterized by significant variability. It indicates about necessary to personalize cells sensitivity to chemotherapeutic effects ex vivo . Moreover, a certain sensitivity of donor’s cells to the studied anticancer drugs (except for imatinib) was found. It should be taken into account under using chemotherapy protocols during treatment of individual patient. For the possibility of personalized accounting of the cells response of ALL patients to chemotherapy, a change in their redox balance can be used as a prognostic indicator.
acute lymphoblastic leukemia, reactive oxygen species, low molecular weight antioxidants, cell viability, anticancer drugs
1. Gaynor J, Chapman D, Little C, et al. A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. Journal of Clinical Oncology, 1988, vol. 6, no. 6, pp. 1014-1030.
2. Schellong G., Potter R., Bramswig J. et al. High Cure Rates and Reduced Long-Term Toxicity in Pediatric Hodgkins Disease: The German -Austrian Multicenter Trial DAL-HD-90. J. Clin. Oncol., 1999, vol.17, no. 12, pp. 3736-3744.
3. Brinkmann V., Geiger T., Alkan S.et al.Interferon-alfa increases the frequency of interferon gamma-producing human CD4+ T-cells. J. Exp. Med., 1993, vol. 178, pp. 1655-1663.
4. Jansen J.H., de Ridder M.C., Geertsma W.M. et al.Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-transretinoic acid and granulocyte colony-stimulating factor. Blood, 1999, vol. 94, no. 1, pp. 39-45.
5. Zhou F., Shen Q., Claret F. Novel roles of reactive oxygen species in the pathogenesis of acute myeloid leukemia. J. Leuk.e Biol., 2013, vol. 3, no. 94, pp. 423-429.
6. Trachootham D. et al. Selective killing of oncogenic transformed cells through ROS-mediated mechanism by β-phenylethyl isothiocyanates. Cancer Cell., 2006, vol. 10, pp. 241-252.
7. Carew J.S. et al. Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to udarabine. Leukemia, 2004, vol. 18, pp. 1934-1940.
8. Hileman E.O. et al.Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol, 2004, vol. 53, pp. 209-219.
9. Trachootham D. et. al. Effective elimination of fludarabine-resistant CLL cells by PEITC through. Blood, 2008, vol. 112, no. 5, pp. 1912-1922.
10. Svirnovskiy A.I. i dr. Lekarstvennaya chuvstvitel'nost' leykoznyh kletok ex vivo i prognozirovanie otveta pacientov s hronicheskim limfocitarnym leykozom na terapiyu. Zdravoohranenie, 2010, № 3, c. 57-60. @@Svirnovsky A.I. et al. Drug sensitivity of leukemic cells ex vivo and predicting the response of patients with chronic lymphocytic leukemia to therapy. Healthcare, 2010, no. 3, pp. 57-60. (In Russ.)
11. Cramer P., Hallek M. Initial therapy of chronic lymphocytic leukemia. Semin. Oncol., 2016, № 43, vol. 2, pp. 241-250.
12. Haugland R.P. Handbook of fluorescent probes and research products. 9-nd Edition. USA: Molecular Probes Inc, 2002, 964 p.
13. Vladimirov Yu.A. Narushenie bar'ernyh svoystv vnutrenney i naruzhnoy membran mitohondriy, nekroz i apoptoz. Biologicheskie membrany, 2003, t. 19, № 5, c. 356-377. @@Vladimirov Yu.A. Violation of the barrier properties of the inner and outer membranes of mitochondria, necrosis and apoptosis. Biological membranes, 2003, vol. 19, no. 5, pp. 356-377. (In Russ.)
14. Veerman A., Pieters R. Annotation. Drug sensitivity assay in leukaemia and lymphoma. Brit. J. Haem., 1990, vol. 74, no. 4, pp. 381-384.
15. Sigma Aldrich [Electronic resource] Antioxidant Assay Kit, 2012.
16. Tamashevskiy A.V. i dr. Okislitel'nyy stress v limfocitah pri hronicheskom limfocitarnom leykoze, inducirovannyy protivoopuholevymi preparatami. Izvestiya NAN Belarusi. Ser. biol. Nauk, 2010, № 3, c. 62-66. @@Tamashevsky A.V. et al. Oxidative stress in lymphocytes in chronic lymphocytic leukemia, induced by anticancer drugs. Bulletin of the National Academy of Sciences of Belarus. Ser. biol. Nauk, 2010, no. 3, pp. 62-66. (In Russ.)
17. Svirnovskiy A.I. Hronicheskiy limfocitarnyy leykoz: paradigmy i paradoksy. Medicinskie novosti, 2008, № 13, c. 7-19. @@Svirnovsky A.I. Chronic lymphocytic leukemia: paradigms and paradoxes. Medical News, 2008, no. 13, pp. 7-19. (In Russ.)
18. Chandra J., Samali A., Orrenius S. Triggering and modulation of apoptosis by oxidative stress. Free Radic. Biol. Med., 2000, vol. 29, pp. 323-333.
19. Barzilai A., Yamamoto K. DNA damage responses to oxidative stress. DNA Repair (Amst), 2004, vol. 3, pp. 1109-1115.
20. Fleury C., Mignotte B., Vayssiere J.L. Mitochondrial reactive oxygen species in cell death signaling. Biochimie, 2002, vol. 84, pp. 131-141.
21. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J. Natl. Cancer Inst., 1999, vol. 91, pp. 861-868.
22. Moore A., Pinkerton R. Vincristine: can its therapeutic index be enhanced? Pediatr. Blood, 2009, vol. 53, pp. 1180-1187.
23. Ricci F. et al. Fludarabine in the treatment of chronic lymphocytic leukemia: a review. Ther. Clin. Risk Manag., 2009, vol. 5, pp. 187-207.
24. Baptista M.J. et al. Differential gene expression profile associated to apoptosis induced by dexamethasone in CLL cells according to IGHV/ZAP-70 status. Clin. Cancer Res., 2012, vol. 18, no. 21, pp. 5924-5933.
25. Lewandowski K. et al. B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib. Case Rep. Med., 2016, p. 9806515.
26. Uss A.L., Zmachinskiy V.A. Lechenie recidivov i rezistentnyh form limfomy Hodzhkina. Materialy VI Rossiyskoy Onkologicheskoy konferencii 6-28 noyabrya 2002 g. Moskva, c. 55-57. @@Uss A.L., Zmachinsky V.A. Treatment of recurrent and resistant forms of Hodgkin's lymphoma. Materials of the VI Russian Oncological Conference November 6-28, 2002 Moscow, pp. 55-57. (In Russ.)
