PRECLINICAL EVALUATION OF DICHLOROBIS(1-PHENYLBUTANE-1,3-DIONATO)TITANIUM(IV) AND BUDOTITANE - 2 REPRESENTATIVES OF THE NEW CLASS OF ANTITUMOR-ACTIVE BIS-BETA-DIKETONATO METAL-COMPLEXES

  • 1 January 1986
    • journal article
    • research article
    • Vol. 36-2  (12) , 1822-1828
Abstract
The antitumor-active bis-.beta.-diketonato metal complexes dichlorobis(1-phenylbutane-1,3-dionato)titanium (IV) and diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV) (prop. INN: budotitane) are active against several transplantable tumors. Activity was demonstrated by treating the intramuscularly, subcutaneously and intraperitoneally transplanted sarcoma 180 tumor and against the Walker 256 carcinosaracoma as well. In these models an increase in survival time up to T/C-values of 200 to 300% (T/C = (median survival time of treated animals to that of controls) .times. 100) and reduction of tumor weight to 30 or 0%, compared with the untreated control animals, was demonstrated. The therapy of the leukemias P 388 and L 1210 turned out to be statistically significant but only marginal in terms of increase in survival time (T/C .apprx. 130%). The toxicological experiments demonstrate single doses up to 40 mg/kg, given intravenously in female SD-rats, as to be well tolerable. The dose 80 mg/kg caused lethality in the range between 14 and 50% in 3 independent experiments. The spontaneously dying animals showed hemorrhagic pleural effusions and hemorrhagic oedematous areas of the lung. Histopathologically hyperemia and multiple focal necroses of the liver were found. The described lung toxicity was found only in high, single and lethal doses. Chronic doses of 10 to 20 mg/kg caused only mild liver toxicity. The laboratory parameters were increased in the values of the enzymes GOT, GPT and LDH. No evidence of myelosuppression was found in the peripheral blood. No emesis-causing behaviour could be detected with the compound budotitane in a pigeon model. With respect to its favourable toxicological and therapeutical properties, the compound budotitane was selected for clinical studies.

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