The effect of a single injection of doxorubicin, 8-day administration of two 5-hydroxypyrimidine derivatives, SNK-411 (2-Isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (hydrochloride of 2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine), on metastases, lifespan and serum cytokines has been investigated in С57ВL/6 mice after removal of a primary tumor node of Lewis lung carcinoma (LLC). LLC cells (1×106) were injected in the footpad of right hind feet of mice in control and experimental groups; after 14 days of tumor development the hind feet with the tumor were amputated at the ankle level. One hour before the amputation mice received a single injection of doxorubicin (4 mg/kg) and 8-day therapy with the 5-hydroxypyrimidine derivatives started. SNK-578 monotherapy was performed at a dose of 10 mg/kg administered intraperitoneally (i.p.). SNK-411 was administered per os at a dose of 25 mg/kg. In the case of combined therapy mice also received a single injection of doxorubicin (4 mg/kg; i.p.). The metastasis inhibition index in mice-treated with SNK-411 and SNK-578 were 53.3% as compared with control mice (with removed tumor). The mice-treated with SNK-411, doxorubicin, and the combination SNK-578 + doxorubicin had lifespan increased by 60.2%, 53.9%, and 42.9%, respectively. A single injection of doxorubicin, the course administration of the 5-hydroxypyrimidine derivative alone and in combination with single injection of doxorubicin completely decreased serum levels of the prooncogenic Th2-cytokines IL-4, and IL-6 and significantly decreased the level of the Th2-cytokine IL-5. Administration of doxorubicin, SNK-411 and SNK-578 did not influence serum concentration of Th1-cytokine interferon gamma (IFN-γ). These data confirm our previous findings that administration of the compounds studied decreased concentrations of prooncogenic IL-4 and IL-6 in tumor-bearing mice with LLC and had no effect on concentrations of the Th1-cytokine IFN-γ.
Izucheno vliianie na metastazirovanie, prodolzhitel'nost' zhizni i kontsentratsiiu tsitokinov v syvorotkakh krovi mysheĭ posle udaleniia pervichnogo opukholevogo uzla kartsinomy legkogo Lewis (LLC), odnokratnogo vvedeniia mysham linii S57VL/6 doksorubitsina, 8-dnevnogo vvedeniia proizvodnykh 5-oksipirimidina SNK-411 (2-izobutil-4,6-dimetil-5-oksipirimidin) i SNK-578 (khlorgidrat 2-izobutil-4,6-dimetil-5-oksipirimidina), razdel'no, a takzhe v sochetanii s odnokratnym vvedeniem doksorubitsina. Kletki LLC v kontsentratsii 1×10⁶ vvodili v podushechku pravoĭ zadneĭ stopy zhivotnym kontrol'nykh i opytnykh grupp, po istechenii 14 dneĭ lapki s opukhol'iu amputirovali po golenostopnomu sustavu. Za 1 ch do amputatsii lapki s pervichnym opukholevym uzlom odnokratno vvodili doksorubitsin v doze 4 mg/kg i nachinali 8-dnevnuiu monoterapiiu SNK-578 v doze 10 mg/kg vnutribriushinno (v/br), SNK-411 v doze 25 mg/kg peroral'no i v sochetanii s odnokratnym v/br vvedeniem doksorubitsina v doze 4 mg/kg. Pri vvedenii SNK-411 i SNK-578 indeks ingibirovaniia metastazirovaniia sostavil po 53,3% po sravneniiu s kontrolem s udalennoĭ opukhol'iu. V gruppe zhivotnykh, kotorym vvodili SNK-411, otmecheno uvelichenie prodolzhitel'nosti zhizni na 60,2%, doksorubitsin — na 53,9%, SNK-578 s doksorubitsinom — na 42,9%. Odnokratnoe vvedenie doksorubitsina, 8-dnevnoe vvedenie proizvodnykh 5-oksipirimidina v sochetanii s odnokratnym vvedeniem doksorubitsina polnost'iu snizhalo soderzhanie proonkogennykh Th2 tsitokinov IL-4 i IL-6 v obraztsakh syvorotki krovi zhivotnykh opytnykh grupp i znachimo umen'shalo soderzhanie Th2 tsitokina IL-5. Vvedenie doksorubitsina, SNK-411 ili SNK-578 ne snizhalo kontsentratsiiu Th1 tsitokina IFN-γ, chto podtverzhdaet rannee poluchennye nami dannye ob umen'shenii kontsentratsii Th2 tsitokinov IL-4 i IL-6 u mysheĭ c LLC, i ob otsutstvii negativnogo vliianiia na Th1 tsitokin IFN-γ v gruppakh zhivotnykh, poluchavshikh issleduemye soedineniia.
Keywords: doxorubicin; interleukins; lung cancer; metastasis; pyrimidines; survival analysis.