Abstract:
Introduction: Cancer is a big challenge of the 21 century, whose defeat requires efficient antitumor drugs.
Objectives: The paper aims to investigate the synergistic effect of two structural building blocks, phenothiazine
and poly(ethylene glycol), towards efficient antitumor drugs.
Methods: Two PEGylated phenothiazine derivatives were synthetized by attaching poly(ethylene glycol)
of 550 Da to the nitrogen atom of phenothiazine by ether or ester linkage. Their antitumor activity has
been investigated on five human tumour lines and a mouse tumor line as well, by determination of
IC50. The in vivo toxicity was determined by measuring the LD50 in BALB/c mice by the sequential
method and the in vivo antitumor potential was measured by the tumours growth test. The antitumor
mechanism was investigated by complexation studies of zinc and magnesium ions characteristic to the
farnesyltransferase enzyme, by studies of self-aggregation in the cells proximity and by investigation
of the antitumor properties of the acid species resulted by enzymatic cleavage of the PEGylated derivatives.
Results: The two compounds showed antitumor activity, with IC50 against mouse colon carcinoma cell
line comparable with that of the traditional antitumor drugs 5-Fluorouracil and doxorubicin. The phenothiazine
PEGylation resulted in a significant toxicity diminishing, the LD50 in BALB/c mice increasing
from 952.38 up to 1450 mg/kg, in phenothiazine equivalents. Both compounds inflicted a 92% inhibition of the tumour growth for doses much smaller than LD50. The investigation of the possible tumour inhibition
mechanism suggested the nanoaggregate formation and the cleavage of ester bonds as key factors
for the inhibition of cancer cell proliferation and biocompatibility improvement.
Conclusion: Phenothiazine and PEG building blocks have a synergetic effect working for both tumour
growth inhibition and biocompatibility improvement. All these findings recommend the PEGylated phenothiazine
derivatives as a valuable workbench for a next generation of antitumor drugs.
