THE STUDY OF ANTITUMOR ACTIVITY OF PHENYLBUTYRATE IN COMBINATION WITH 5-FLUOROURACIL ON MODEL OF EHRLICH CARCINOMA

Introduction. Until now, the search continues for new anticancer drugs with high efficacy and low toxicity profile. One promising class of anticancer agents that meet these requirements are histone deacetylase inhibitors (HDAC), in particular, sodium phenylbutyrate (PB). Aim. Experimental estimate of the dose and time dependence of the antitumor activity, and tolerability during prolonged oral administration of PB in combination with 5-fluorouracil (5-FU) on Ehrlich carcinoma model. Materials and methods. The animals were divided into 6 groups (n = 20 mice): 1^st (control group) - received normal drinking water, 2^nd - PB (800 mg/kg), an aqueous solution instead of drinking water, 3^th - 5-FU (200 mg/kg), as the maximum tolerated dose (MTD), 4^th - PB +5-FU (800, 200 mg/kg), 5^th - 5-FU(100 mg/kg) intraperitoneally, once, and 6^th - PB + 5-FU (800,100 mg/kg). The drugs were administered sequentially 48 hours after inoculation for 14 days. Results. The most pronounced inhibition of tumor growth was observed in the combined treatment on the 14^th day after inoculation in group PB + 5-FU (200 mg/kg) and PB + 5-FU (100 mg/kg), tumorgrowth inhibition (TGI) = 92-96 % and 83-90 % respectively, compared to controls. Comparison of combined treatment with monotherapy showed a significant increase in TGI = 63-72 %, and with respect to PB and 54-57 % relative to 5-FU, which indicating of synergistically antitumor effect, which persisted after treatment on level of TGI = 72-87 % (p < 0.05), which persisted for 21 days on level of TGI = 72-87%. Prolonged oral administration PB in combination with 5-FU significantly improved tolerance and increased lifespan of the animals at 33 %, which was 1.5 times more, compared with monotherapy. Conclusions. These data allow to conclude that a rational combination of HDAC with cytotoxic agent is able to overcome the resistance mechanism of tumor cells and lead to a synergistic antitumor effect and lower toxicity.

фенилбутират, 5-фторурацил, карцинома Эрлиха, ингибитор деацетилазы гистонов, комбинированная терапия, phenylbutyrate, 5-fluorouracil, Ehrlich carcinoma, tumor growth inhibition, combined therapy

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