Creation of new combinations of antitumor remedies (experimental study)

Khavych O., Sharykina N., Grygorieva T., Meshkova N., Zakharenko V.

O. Khavych, N. Sharykina, N. Meshkova, V. Zakharenko

State Institution “Institute of Pharmacology and Toxicology of NAMS of Ukraine”, Kyiv, Ukraine

Introduction: Development of a new combination of antitumor remedies replacing one or two components in well-known combinations by preparations with more selective antitumor activity is one of approaches to improve effectiveness of cancer pharmacotherapy. Aim: To create new combinations of antitumor drugs on a basis of initial combinations from standard treatment protocols for cancer replacing cyclophosphamide, fluorouracil and bonefos by chlofiden, fludinat and mebifon, which were developed in SI “IPT NAMSU”. Materials and Methods: Toxicological and histological methods and method of tumor allografts were used. Melanoma B16 and Lewis lung carcinoma (3LL) were used as tumor models. Drugs were injected intraperitonially 24 hours after tumor implantation. Drug dosage for mice based on single dose for human was calculated using rapid extrapolation method. Results: The substitution of phosphorylated chlorethylamine chlofiden and fludinat for traditional combinations of cyclophosphamide and fluorouracil restored high antitumor activity of initial combinations but reduced their toxicity (chlofiden does not induce nephro- and hepatotoxicity, unlike cyclophosphamide; toxicity of fludinat is 3.3 fold lower than that of fluorouracyl). Thus, new remedies have more selective antitumor action. In melanoma B16, combination of doxorubicine, 3.0 mg/kg, cisplatine, 3.0 mg/kg and cyclophosphamide, 30.0 mg/kg, caused 80.5% of tumor growth inhibition, while replacement of cyclophosphamide by chlofiden, 30.0 mg/kg, in this combination enhanced tumor inhibition up to 85.9%. Doxorubicine, 3.0 mg/kg, cyclophosphamide, 30.0 mg/kg and fluorouracil, 37.0 mg/kg caused 90.2% of 3LL growth inhibition, meanwhile the same combination with fludinat, 37.0 mg/kg, instead of fluorouracil showed 85.9% of 3LL growth inhibition. Toxicity of mebifon and bonefos is similar, but mebifon showed higher antitumor activity than bonefos (72.0% and 37.4% of B16 growth inhibition respectively). Combination of dacarbazine, 60.1 mg/kg, cisplatin, 1.5 mg/kg, vinblastine, 0.2 mg/kg and bonefos, 14.0 mg/kg inhibited growth of melanoma B16 by 81.7%, the substitution of mebifon, 14.0 mg/kg, for bonefos resulted in 91.6% of B16 growth inhibition (10% higher than initial combination). Conclusions: On the basis of combinations from standard cancer treatment protocols of NCI of Ukraine, there were developed combinations of anticancer remedies with replacement of cyclophosphamide, fluorouracil and bonefos by chlofiden, fludinat and mebifon. Combinations of chlofiden and fludinat had the same antitumor activity and were less toxic than standard combinations. The replacement of bonefos by mebifon enhanced antitumor activity of initial combination.

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