Antineoplastic activity of three ruthenium derivatives against chemically induced colorectal carcinoma in rats

Summary

The antineoplastic activity of the ruthenium complexestrans-imidazolium[tetrachlorobisimidazoleruthenate(III)], HIm(RuIm₂Cl₄),trans-indazolium-[tetrachlorobis(1H-indazole)ruthenate(III,N ²)], HInd [RuInd₂Cl₄(N ²)], andtrans-indazolium[tetrachlorobis(2H-indazole)ruthenate(III,N ¹)], HInd[RuInd₂Cl₄-(N¹)] was assessed in acetoxymethylmethylnitrosamine-induced autochthonous colorectal carcinomas of Sprague-Dawley rats. The model is not sensitive to clinically established antineoplastic agents, including cisplatin. An exception is the combination therapy with 5-fluorouracil/leucovorin, which shows moderate activity against the tumour model. In contrast to this general trend, the new substances were all active against this tumour. HIm(RuIm₂Cl₄) was very effective at all dosages applied (7.5 mg/kg, 5.3 mg/kg, and 3.8 mg/kg), as indicated by percentage treated/control (T/C values of 23%, 34.5%, and 44%. Toxicity was considerable as shown by a body weight change of −30%, −19%, and −9%. Nevertheless, the medium dose seems to be the optimum in terms of mortality (0% vs 15% in the control group), whereas at the highest dose, mortality increased as a result of substance toxicity, and at the lowest dose mortality increased through tumor growth combined with substance toxicity.

HInd[RuInd₂Cl₄(N²)] showed high efficacy at the highest dosage of 13 mg/kg, reaching a T/C value of 27% combined with 0% mortality versus 15% in the control group. In equimolar dosages (10 mg/kg, 7.1 mg/kg and 5.1 mg/kg), the compound is not as active as HIm-(RuIm₂Cl₄), as indicated by T/C values of 50.2%, 45.7%, and 38.6%. HInd[RuInd₂Cl₄(N¹)] was slightly but not significantly better than HInd[RuInd₂Cl₄(N²)] at a dosage of 7.1 mg/kg and is advantageous over combination therapy with 5-fluorouracil and leucovorin (20/20 mg/kg) in terms of efficacy (T/C=37.6% versus 44.7%) and mortality (6% versus 33.3%).