oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2017-16-5-27-35oncotomsk-610Research ArticleЛАБОРАТОРНЫЕ И ЭКСПЕРИМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯLABORATORY AND EXPERIMENTAL STUDIESИСПОЛЬЗОВАНИЕ ПИРИДОКСИНА ДЛЯ ПОВЫШЕНИЯ ПРОТИВООПУХОЛЕВОЙ АКТИВНОСТИ МЕТИОНИН-ГАММАЛИАЗЫ НА МОДЕЛЯХ ПЕРЕВИВАЕМЫХ ОПУХОЛЕЙ МЫШЕЙUSE OF PYRIDOXINE TO INCREASE ANTICACNER ACTIVITY OF METHIONINE-GAMMA-LYASE IN MURINE CANCER MODELSДавыдовД. Ж.DavydovD. Zh.

лаборант-исследователь

SPIN-код: 6543-3596

115478, г. Москва, Каширское шоссе, 23

 

23, Kashirskoe shosse, 115478-Moscow

davydov.online@gmail.comМорозоваЕ. А.MorozovaЕ. А.

кандидат химических наук, старший научный сотрудник

119991, г. Москва, ул. Вавилова, 32

 

 

32,Vavilova Street, 119991-Moscow

elmorozova@yahoo.comКомароваМ. В.KomarovaМ. V.

кандидат биологических наук, доцент кафедры лазерных и биотехнических систем

SPIN-код: 4359-2715

443099, г. Самара, ул. Чапаевская, 89

 

89, Chapaevskaya Street, 443099-Samara

marinakom@yandex.ruАнуфриеваН. В.AnufrievaN. V.

младший научный сотрудник

 SPIN-код: 3212-7374

119991, г. Москва, ул. Вавилова, 32

 

32,Vavilova Street, 119991-Moscow

lazyfox@rambler.ruЗавильгельскийГ. Б.ZavilgelskyG. B.

доктор биологических наук, старший научный сотрудник

117545, г. Москва, 1-й Дорожный проезд, 14

 

 

1, Fist Dorozhny proezd, 117545-Moscow

gzavilgel@yandex.ruМануховИ. В.ManukhovI. V.

доктор биологических наук, старший научный сотрудник лаборатории молекулярной генетики

SPIN-код: 3711-4901

117545, г. Москва, 1-й Дорожный проезд, 14

141700, г. Долгопрудный, Институтский пер., 95

 

1, Fist Dorozhny proezd, 117545-Moscow, Russia

9, Institutsky per., 141700-Dolgoprudny, Moscow region

manukhovi@mail.ruДемидкинаТ. В.DemidkinaT. V.

заведующая лабораторией химических основ биокатализа

119991, г. Москва, ул. Вавилова, 32

32,Vavilova Street, 119991-Moscow

ТрещалинаЕ. М.TreshchalinaЕ. М.

115478, г. Москва, Каширское шоссе, 23

доктор медицинских наук, старший научный сотрудник

SPIN-код: 7230-1364 

23, Kashirskoe shosse, 115478-Moscow

treshalina@yandex.ruПокровскийВ. С.PokrovskyV. S.

доктор биологических наук, старший научный сотрудник лаборатории молекулярной генетики

SPIN-код: 3711-4901

115478, г. Москва, Каширское шоссе, 23

 

23, Kashirskoe shosse, 115478-Moscow

manukhovi@mail.ruФГБУ «РОНЦ им. Н.Н. Блохина» Минздрава РФРоссияN.N. Blokhin Russian Cancer Research CenterRussian FederationФГБУН «ИМБ им. В.А. Энгельгардта» РАНРоссияV.A. Engelgardt Institute of Molecular BiologyRussian FederationФГБОУ ВО «СамГМУ» Минздрава РФРоссияSamara State Medical UniversityRussian FederationФГУП «ГосНИИгенетика»РоссияState Research Institute of GeneticsRussian FederationФГУП «ГосНИИгенетика»; ФГБОУ ВО «МФТИ», Лаборатория молекулярной генетикиРоссияState Research Institute of Genetics; Laboratory of Molecular Genetics, Dolgoprudny, Moscow regionRussian Federation2017141120171652735Copyright © Давыдов Д.Ж., Морозова Е.А., Комарова М.В., Ануфриева Н.В., Завильгельский Г.Б., Манухов И.В., Демидкина Т.В., Трещалина Е.М., Покровский В.С., 20172017Давыдов Д.Ж., Морозова Е.А., Комарова М.В., Ануфриева Н.В., Завильгельский Г.Б., Манухов И.В., Демидкина Т.В., Трещалина Е.М., Покровский В.С.Davydov D.Z., Morozova Е.А., Komarova М.V., Anufrieva N.V., Zavilgelsky G.B., Manukhov I.V., Demidkina T.V., Treshchalina Е.М., Pokrovsky V.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/610

Приведены экспериментальные данные монотерапии и комбинированной терапии моделей перевиваемых опухолей мышей препаратами метионин-γ-лиазы (МГЛ) и пиридоксина гидрохлорида. Изучены МГЛ Clostridium sporogenes и Citrobacter freundii. Использованы перевиваемые модели опухолей мышей: карцинома легкого Льюис (LLC), меланома В16, лимфолейкоз P388, лимфолейкоз L1210, лимфаденоз Фишера L5178y. На моделях P388, L5178y МГЛ не показала противоопухолевой активности ни в монорежиме, ни в сочетании с пиридоксином. На модели L1210 было получено пограничное увеличение продолжительности жизни (УПЖ) 22 %, р=0,035 при применении МГЛ C. sporogenes в дозе 2000 Е/кг 11-кратно внутрибрюшинно с интервалом 12 ч. На LLC показано, что на 1-е сут после окончания лечения одновременное внутрибрюшное (в/б) введение МГЛ C. sporogenes 400 Е/кг 4-кратно с интервалом 48 ч и пиридоксина в дозе 250 мг/кг вызывало ТРО=55 % (р<0,001), монотерапия МГЛ или пиридоксином в аналогичных дозах и режимах применения вызывала ТРО=24 % (р=0,263) и 21 % (р=0,410) соотетственно. При попарном сравнении: комбинированная терапия МГЛ + пиридоксин против монотерапии МГЛ в аналогичном режиме р=0,061, против монотерапии пиридоксином р=0,031. На LLC МГЛ C. freundii 200 Е/кг 4-кратно с интервалом 48 ч и пиридоксина в дозе 500 мг/кг одновременно на 9-е сут после окончания лечения вызывало ТРО=50 % (р=0,001), при этом монотерапия МГЛ в разовой дозе 400 Е/кг или пиридоксином в аналогичном режиме применения вызывала ТРО=+5 % (р=0,991) и 4 % (р=0,998) соответственно. При попарном сравнении: комбинированная терапия МГЛ 200 Е/кг + пиридоксин против монотерапии МГЛ 400 Е/кг в аналогичном режиме р<0,001, против монотерапии пиридоксином р=0,003. На модели меланома B16 МГЛ 2000 в/б + пиридоксин 300 мг/кг вызывает ТРО 56 % на 1-е сут (р=0,045) и 35 % на 3-и сут (р=0,038). При комбинированной терапии МГЛ + пиридоксин последний значимо повышал противоопухолевую активность МГЛ в сочетаниях: МГЛ 1000 Е/кг в/б и МГЛ 1000 Е/кг в/б + пиридоксин 300 мг/кг ТРО=45 % (р=0,034) на 3-и сут после окончания лечения. При внутривенном введении МГЛ 500 Е/кг и МГЛ 500 Е/кг + пиридоксин последний повышал эффективность лечения: максимальное ТРО 50 % на 1-е сут после окончания лечения (р=0,085, различие не достоверно) и 21 % на 3-и сут после окончания лечения ТРО 22 % (р=0,965, различие не достоверно).

Разовая максимальная переносимая доза при многократном в/б введении составила 2000 Е/кг, одновременное применение пиридоксина не усугубляло токсичности МГЛ. Таким образом, LLC и меланома В16 обладают чувствительностью к терапии МГЛ. Одновременное введение пиридоксина на модели LLC и В16 достоверно повышает её эффективность.

We presented results of monotherapy and combination therapy of transplantable murine tumor models using methionine-gamma-lyase (MGL) and pyridoxine hydrochloride. We studied MGL from Clostridium sporogenes and Citrobacter freundii. We used Lewis lung carcinoma (LLC), melanoma B16, leukemias P388 and L1210 and Fisher lymphadenosis L5178y. Neither monotherapy with MGL nor combination of MGL and pyridoxine demonstrated antitumor activity against P388 and L5178y. In the murine L1210 leukemia model, MGL C. sporogenes injected intraperitoneally in the dose of 2000 U/kg, 11 times with a 12-hour interval increased the life span of mice (ILS=22 %, р=0.035). In the LLC model, the combination of MGL C. sporogenes at a dose of 400 U/kg, i.p., 4 times with a 48-hour interval and pyridoxine at a dose of 250 mg/kg led to tumor growth inhibition (TGI=55 %, р<0.001) on the first day after the completion of treatment. Monotherapy with MGL or pyridoxine in the same regimens resulted in a 24 % TGI (р=0.263) or 21 % TGI (р=0.410), respectively. In a pair-wise comparison of treatments, MGL + pyridoxine was more effective compared to MGL used alone (р=0.061) and MGL + pyridoxine was more effective then pyridoxine alone (р=0.031). MGL from C. freundii at a dose of 200 U/kg, 4 times with a 48-hour interval plus pyridoxine at a dose of 500 mg/kg injected on day 9 after the completion of treatment led to 50 % TGI, whereas MGL monotherapy at a single dose of 400 U/kg or pyridoxine monotherapy in the same regimen showed 5 % TGI (р=0.991) and 4 % TGI (р=0.998), respectively. The pair-wise comparison showed that MGL (200 U/kg) + pyridoxine was more effective than MGL (400 U/ kg) alone (р<0.001) and pyridoxine alone (р=0.003). In the B16 model, the combination of MGL injected i.p at a dose of 2000 U/kg and pyridoxine at a dose of 300 mg/kg showed 56 % TGI on day 1after the completion of treatment (р=0.045) and 35 % TGI on day 3 (р=0.038). Pyridoxine significantly increased the anticancer effect of MGL: MGL 1000 U/kg i.p and MGL 1000 U/kg i.p. + pyridoxine 300 mg/kg led to TGI=45 % (р=0.034) on day 3 after the completion of treatment. Single maximum tolerated dose after multiple i.p. administration was defined as 2000 U/kg, simultaneous administration of pyridoxine did not increase the toxicity of MGL. In conclusion, LLC and B16 are sensitive to MGL treatment, and pyridoxine may increase the efficacy of MGL.

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The authors declare that there are no conflicts of interest present.