Survival and Histopathological Study of Animals Bearing Ehrlich Tumor Treated With a Rhodium(II) Amidate

The survival of 90% of a tumor-bearing population treated with the complex Rh2 (CF3CONH)4 was examined and the pharmacological parameter Surv90 determined. Histopathological alterations raised for this drug in several tissues were studied in Balb-c mice. A Surv90 dose of 3.8x 10-5 mol/kg was found.


INTRODUCTION
The use of rhodium (II) dimers as possible antitumoral agents has been investigated, and the recent literature reports a number of examples of these complexes which could overcome the toxicities of the carboxylates initially proposed [1]. Relatively few data are available about the biodistribution, pharmacokinetics and histopathology of the rhodium (II) dimer complexes. Souza and coworkers [2] investigated the distribution of rhodium in mice submitted to treatment with the adduct of rhodium propionate and sodium isonicotinate, by means of ICP-AES. Craciunescu and coworkers [3] performed a study of the biological activity, nephro, hepato and hematotoxicity of adducts of rhodium(II) and iridium(II) dimers with classical organic antimalarial drugs. Also, these authors described the renal histopathology atter the administration of the complex Rhz(CH3COO)4(mepacrine)2.
Recently, the pharmacological parameters ICs0 (against Ehrlich ascites and U937 and K562 human leukemia cells) and LDs0 (in male Balb-c mice) of the complex Rhz(CF3CONH)4 (tfacam) were reported. The LDso of tfacam was close to the value obtained for cisplatin in similar conditions (cf. [4] and references therein]. These results encouraged subsequent studies in the biological destinations of this and other rhodium (II) complexes. In this work, the pharmacological parameter Survo was determined (def'med as the dose that allows the survival of 90% of the tumor-treated animals [5]) of the drug tfacam. The histopathological study of brain, blood, kidney, spleen, liver, lungs, bone marrow, testes and ovary tissues from Balb-c mice treated with this complex are also presented.

MATERIALS AND METHODS
The complex tfacam was synthesized and suspended in an aqueous solution (5% of TweenTM-80) as described in [4]. The mice were sacrificed to collect tissue (heart, lungs, blood, liver, kidneys, testes, ovary, brain and bone marrow) after 25 days. Those parts were kept in a 10% formol solution and then in blocks of paraffin and finally in slides to be observed in hematoxylin-eosin coloration in an optic microscope. No animals died for toxic effects of the drug during this period. RESULTS a) Survival tes.__.2t: Table shows the counts after the experimental period. Vol. 6, No. I, 1999 Survival and Histopathological Study of Animals Bearing Ehrlich Tumor Treated with a Rhodium(II) Amidate only Tween"--80 From these data, it was found a Survgo value of 3.8x 10 .5 mol/kg for the complex tfacam. b) His_topathological test: No differences were observed between the control group and the group of animals that received only TweenTM-80 solution.
The mice that received the rhodium drug showed the abnormalities reported in Table II.  [3] used half of the LDs0 of the drug Rh2(CH3COO)4(mepacrine): and found alterations described as light to moderate nephrotoxicity, and no hepatotoxicity.
With the i.p. injection of tfacam solution in the range of 1.0 to 2.6x10 .5 mol/kg, a linear dependence between the survival rate and the dose was obtained. The extrapolation to 90% afforded us the value of Survo 3.8x10 5 mol/kg. However, this dose is close to the LDs0 of the drug (4.8x10 5 mol/kg [4]). The injection of the Survgo dose in five animals didn't cause any deaths. The toxic effects appeared mainly in the liver and kidneys.