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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.

The effects of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine chlorohydrate) on the tumor growth and survival of male C57BL/6 mice with transplanted Lewis lung epidermoid carcinoma (LLC) were studied in animals receiving intraperitoneal treatment on days 2-15 of tumor development. Compound SNK-578 in a dose of 10 mg/kg significantly inhibited tumor growth (by 3.6 times; 72.2%) in 7 days after the treatment was discontinued, while compound SNK-411 in a dose of 25 mg/kg only negligibly reduced tumor volume (by 41.7%). A combination of course of SNK-411 (25 mg/kg) and single intraperitoneal dose of doxorubicin (4 mg/kg) significantly inhibited the tumor growth (by 2.2 times; 55.2%), while the combination of SNK-578 (10 mg/kg) with doxorubicin (4 mg/kg) was in fact ineffective. The median survival of animals with untreated LLC was 28 days. Median survival of mice injected with SNK-578 (10 mg/kg) was 43 days, hence, the lifespan of mice with LLC was by 38.6% longer after the treatment. Two of ten mice in this group developed no tumors.

Experiments on male C57Bl/6 mice with transplantable Lewis lung epidermoid carcinoma were performed to evaluate the effect of early or delayed administration of compound SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) on tumor growth and animal survival. Intraperitoneal injection of SNK-411 in doses of 25 and 50 mg/kg on days 2-8 of tumor growth was followed by significant inhibition of tumor growth (by 1.8 and 2.2 times, respectively, in comparison with the untreated control). Administration of this compound on days 8-15 of tumor development had little effect on tumor growth. SNK-411 in doses of 25 and 50 mg/kg (both dosing regimens) significantly increased survival rate and lifespan of animals with tumors. The drugs for verification of this model (Fluorofur, 400 mg/kg; and doxorubicin hydrochloride, 4 mg/kg) were injected intraperitoneally on days 2-4 and 8-10 of tumor development. Administration of Fluorofur and doxorubicin hydrochloride at the late stage was accompanied by significant inhibition of tumor growth (by 1.6 and 1.4 times, respectively). The increase in the survival rate of animals receiving the cytostatic according to standard dosing regimens was less significant than in experiments with SNK-411.