Abstract
Objective: To study the effect of betulin derivatives combination with 5-fluorouracil or hydrazine sulfate on the ROS generation, the SOD and LDH activity using rat blood, as well as the effect of combination drugs on Ehrlich carcinoma in experiments on mice.
 Methods: We used a chemiluminescence technique to study the ROS generation, and spectrophotometry to determine the MDA level and the SOD and LDH activity. The model of transplanted Ehrlich ascites carcinoma was investigated on mice using a cytological analysis of ascitic fluid cells according to Pappenheim`s method.
 Results: In vitro experiments on rat blood at the doses of 2, 5 and 10 μg per ml revealed the dose-dependent effect of combination drugs on the antioxidant properties. In plasma, the ROS generation and the MDA level increased by 10-300% in comparison with control at the doses of 5 and 10 μg per ml only. Still, the SOD and LDH activity in general increased by 10-130% in comparison with control under the action of the studied combination drugs. The study on mice showed the effectiveness of a combination of triterpenoids and cytostatics in Ehrlich ascites carcinoma therapy. The state and behavior of the animals improved, the volume of ascites fluid decreased by 40-50% after treatment for 10 d.
 Conclusion: The combination of betulin derivatives with cytostatics can be used as antitumor drugs in Ehrlich ascites carcinoma therapy that is due to metabolic plasticity, increased ROS generation in enhanced antioxidant enzyme protection.
Highlights
The high toxicity and many undesirable side effects of anticancer drugs are one of the problems in tumor treatment because it leads to patientslife quality deterioration
The combination of betulin derivatives with cytostatics can be used as antitumor drugs in Ehrlich ascites carcinoma therapy that is due to metabolic plasticity, increased reactive oxygen species (ROS) generation in enhanced antioxidant enzyme protection
Antioxidant and metabolic activities of triterpenoids–betulin (B), betulonic acid (BA), betulin-3,28-diacetate (BDA), and their combinations with cytostatics (B+5-FU, B+hydrazine sulfate (HS), BA+5-FU, BA+HS, BDA+5-FU, BDA+HS) at the doses of 10, 5 and 2 μg per ml by nontumor rat blood were studied in comparison with the control rat blood without treatment taken as 100%
Summary
The high toxicity and many undesirable side effects of anticancer drugs are one of the problems in tumor treatment because it leads to patientslife quality deterioration. In this regard, some novel chemotherapy that will enable to a reduction of anticancer drug doses and side effects is needed. The most promising approach in therapy is the use of natural substances with cytotoxic activity concerning tumor cells but not affecting healthy ones. Such substances include lupane triterpenoids–betulin, betulinic and betulonic acids and their derivatives [1,2,3,4,5,6,7]. Hydrazine sulfate is an insufficiently explored antitumor agent; it inhibits monoamine oxidase and blocks gluconeogenesis by phosphoenol-pyruvate carboxylase [11]. 5-fluorouracil inhibits thymidylate synthase, disrupts the synthesis of the nuclear acids resulting in the apoptosis of tumor cells [12]
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