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Effect of Adjuvants of the Isotiazole Series in Combination with Cisplatin in Chemotherapy of Neuroepithelial Tumors: Experiment, Modeling, Hypothesis
16 Pages Posted: 15 Nov 2021
More...Abstract
Summary: Chemotherapy is one of the main treatment options for cancer, but it is usually accompanied with various side effects. The use of classical drugs combination with synergistic adjuvants can be the solution to this problem, allowing to reduce therapeutic dose while maintaining treatment effectiveness. Elucidating the mechanism of adjuvant action is of key importance for selection of the right agent. Here we examine the system drug-adjuvant to explain observed potentiation effect in practice.
Methods We used the first line drug – cisplatin. Morpholin-4-ium and 4-methylpiperazin-1-ium-1-ium 4,5-dichloro isothiazol-3-carboxylates were selected as adjuvants. We have established potentiating effect of the first one before. Potentiating effect of the second one was found in MTT testing with cisplatin. The study of cisplatin – adjuvant system was carried out by quantum chemical modeling with DFT method CAM-B3LYP/cc-pvdz/LanL2DZ(Pt) level of theory.
Findings Adjuvants of isothiazole series form conjugates with cisplatin. Formation of conjugate leads to relocation of frontier molecular orbitals between cisplatin molecules and adjuvant as well as increase of conjugate’s dipole moment. It results in change of the character of interaction with DNA and increase of biological activity of cisplatin - adjuvant system. This fact allows explaining the effect of adjuvant in used composition.
Interpretation The data obtained are the basis for expanding the studies to include other chemotherapy drugs that are used in modern oncology, as well as other adjuvants’ effects. Such tactics will result in broadening of indications for the use of chemotherapy drugs recommended by international protocols in reduced dosages. Oncologists will have opportunity to use “classical” chemotherapy drugs in combination with synergists for those patients who have not been previously recommended to such prescriptions because of pronounced toxic side effects. Moreover, there is an obvious economic effect of using combination of "classical" chemotherapy drugs with adjuvants in comparison with expensive procedure for development of new chemotherapeutics.
Funding Information: National Academy of Sciences of Belarus, State Scientific Research Program "Convergence 2025",
and KAUST’s Ibex HPC, KAUST Supercomputing Core Lab, Saudi Arabia.
Declaration of Interests: We declare no competing interests.
Keywords: cisplatin, adjuvante, synergism, oncology, chemotherapy, modeling, MTT testing
Suggested Citation: Suggested Citation