Preclinical toxicology and tissue gallium distribution of a novel antitumour gallium compound: tris (8-quinolinolato) gallium (III).

Abstract

Tris (8-chinolinolato) gallium (III) compound (KP46), a new organo-metallic gallium (Ga) complex, has been synthesized for potential use in anticancer therapy. Although this agent has a better bioavailability after oral administration than Ga chloride, it also shows a greater toxicity. The purpose of the present study was to assess the acute and subacute toxicity of KP46, and to determine tissue Ga distribution in healthy Swiss mice. Ga assays were performed by inductively coupled plasma atomic emission spectrometry. In the first experiment, the drug was given by gavage at single doses ranging from 464 to 4640 mg/kg. The LD50 values were 2870 mg/kg (410 mg Ga3+/kg) and 2370 mg/kg (339 mg Ga3+/kg) for males and females, respectively. In the second experiment, KP46 was administered by gavage at 0, 62.5, 125, 250, 500 and 750 mg/kg/day for two weeks (8 animals/dose/sex). The dose of 62.5 mg/kg/day was well tolerated, without deaths, decreased weight gain, or renal, hepatic and hematological toxicities. Higher doses decrease the probability of survival. A significant decrease in the number of white blood cells was noted at doses of 125 mg/kg/day (p<0.05), while hemoglobin, hepatic and renal functions were not affected. At 62.5 mg/kg/day, the Ga concentrations were 7.02 +/- 3.14 microg/g in bone, 3.55 +/- 2.10 microg/g in the liver, 1.81 +/- 0.24 microg/g in the kidneys, 1.77 +/- 1.45 microg/g in the spleen. In lungs, brain, testes and ovaries, the Ga concentrations were under the limit of detection (0.030 ng/g). According to these results, the therapeutic potential of KP46, orally administered, should be evaluated with the dose of 62.5 mg/kg/day. The great affinity of Ga for bone could justify the consideration of KP46 for malignant bone tumours.