CORRELATION BETWEEN SUPEROXIDEAND NO-GENERATING ACTIVITY OF NEUTROPHILS OF PATIENTS WITH COLORECTAL CANCER AND CLINICAL CHARACTERISTICS AND IMPACT ON THE LONG-TERM RESULTS OF COMBINED TREATMENT
Keywords:
colorectal cancer, redox state of neutrophils, effectiveness of treatment.Abstract
Summary. Neutrophils (N) are involved in processes of formation and development of tumor, and towards
they can exhibit both pro- and anti-tumor activity depending on the functional status and stage of neoplasm
development. A crucial importance for tumor regression
belongs to superoxide radicals (SR) and nitrogen oxide
(NO), produced also by N. Aim: to explore features of redox state of N in blood of patients with colorectal cancer
(CRC) under conditions of neoadjuvant radiation therapy with radiomodification (using substrate for biosynthesis of NO) and the correlation of these parameters
and survival of patients. Object and methods: N of blood
of 59 patients with CRC stages II–III (Т2–3N0–2M0)
were investigated. These patients received preoperative
radiotherapy (NRT) (I group), NRT with tegafur potentiation (II group) and NRT on the background of polyradiomodification (III group), followed by a surgery after 4–5 weeks. Superoxide-generating activity of N was
investigated using EPR method, and NO-generating activity — using spin trapping technique. Results: development of CRC is accompanied by an increase in superoxide- and NO-generating activity of N 1,5 and 4,3 times,
respectively. A direct dependence of activity of NADP∙Hoxidase of N on the tumor size (r = 0.54; p <0,01) and
of iNOS — on the type of tumor growth and metastatic
lesion of regional lymph nodes (r = 0.58; p < 0.05; r =
0.49; p < 0.05, respectively) have been revealed. The
average value of activity of NADP∙H-oxidase of N after
NRT in patients, who have survived 3-year period without
recurrence , was 0.23 ± 0.02 nm/105 cells ∙ min; in patients with local R — 0.41±0.03 (p < 0.001); in the cases
with distant metastases — 0.53 ± 0.04 (p < 0.001). Index of activity of this enzyme after the last NRT fraction
has prognostic significance concerning the occurrence of
recurrence and metastases in patients with CRC, who
received the combined treatment. Moreover, the value of
SR generation rate < 0.31 nm/105 cells∙min is a favorable prognostic factor, while the higher value is a factor
of negative prognosis. Conclusions: the use of complex of
polyradiomodification with a preparation of L-arginine
during NRT course causes an increase in levels of superoxide- and NO-generating of activity of N. High rate of
activity of NADP∙H-oxidase of N is a factor of negative
prognosis of survival of patients under conditions of combined treatment.
References
Мальцева ВН, Сафронова ВГ. Неоднозначность роли
нейтрофила в генезе опухоли. Цитология 2009; 6: 467–74.
Gregory AD, Houghton AM. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 2011; 71:
–6.
Klink M, Jastrzembska K, Nowak M, et al. Ovarian cancer
cells modulate human blood neutrophils response to activation in
vitro. Scand J Immunol 2008; 68: 328–36.
Wislez M, Antoine M, Rabbe N, et al. Neutrophils promote
aerogenous spread of lung adenocarcinoma with bronchioloalveolar carcinoma features. Clin Cancer Res 2007; 13: 3518–27.
Knaapen AM, Gungor N, Schins RPF, et al. Neutrophils and
respiratory tract DNA damage and mutagenesis: a review. Mutagenesis 2006; 21: 225–36.
Nozawa H, Chiu Ch, Hanahan D. Infiltrating neutrophils
mediate the initial angiogenic switch in a mouse of multistage carcinogenesis. Proc Nat Acad Sci USA 2006; 103: 12493–8.
Бурлака АП, Сидорик ЕП. Редоксзависимые молекулы
в механизмах опухолевого процесса. К: Наукова думка, 2014.
с.
Granot Z, Henke E, Comen E, et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell
; 20: 300–14.
Bru A, Albertos S, Lopez Garcya-Asenjo JA, et al. Pinning
of tumoral growth by enhancement of the immune response. Phys
Rev Lett 2004; 92 (23): 238101.
Grimm EA, Sikora AG, Ekmekcioglu S. Molecular pathways: inflammation-associated nitric-oxide production as a cancer-supporting redox mechanism and a potential therapeutic target. Clin Cancer Res 2013; 20: 5557–63.
Choudhari SK, ChaudharyM, Bagde S, et al. Nitric oxide
and cancer: a review. World J Surg Oncol 2013; 11: 118.
Ковальчук ЛВ, Игнатьева ГА, Ганковская ЛВ. Иммунология, практикум. М: ГЭОТАР-Медиа, 2010. 194 с.
Бурлака АП, Голотюк ВВ, Вовк АВ та ін. Вплив О2
.
-
та NO-генеруючої активності нейтрофілів на ефективність
неоад’ювантної променевої терапії у хворих на рак прямої
кишки. Онкология 2015; 4: 253–7.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Ass 1958; 53: 457–81.
Голотюк ВВ, Бурлака АП. Патент на корисну модель
№ 102389 UA: «Спосіб прогнозування ефективності комбінованого лікування хворих на рак прямої кишки із врахуванням супероксид-генеруючої активності нейтрофільних
гранулоцитів».
