Alexander Pihl

Pharmacological studies of ricin in mice and humans.

SummaryA highly sensitive enzyme-linked immunosorbent assay (ELISA) for determination of ricin in serum is presented. Using this method it was found that IV-injected ricin disappeared from the plasma of mice and cancer patients according to first-order kinetics.DBA mice were found to be more sensitive to ricin than C3H and B6D2 mice. When mice of the different strains were given the same dose of ricin, the concentrations found in liver, spleen, and kidneys were highest in the most sensitive mice. Ricin disappeared most rapidly from serum of the mice with the highest sensitivity. The inverse correlation between the rate of disappearance of ricin from serum and the tissue concentrations reached may be due to the fact that ricin is rapidly and firmly bound to cell surface receptors.Whole-body autoradiography after IV injection of 125I-labeled ricin showed the highest amount of radioactivity in liver, spleen, and adrenal cortex. Considerable amounts of radioactivity were also present in bone marrow, showing that the lack of myelosuppressive activity of ricin previously found in mice and dogs cannot be accounted for by the failure of ricin to reach the bone marrow.Part of the ricin in the tissues was present in the form of free chains, the highest fraction being present in the liver.In this tissue both the free A-chains and those present in whole ricin were found to be modified. However, the modified A-chains had retained their full capacity to inhibit protein synthesis in vitro.In cancer patients, toxicity appeared at about the same initial serum levels as in the mice, supporting the view that mouse data have a good predictive value for man. At each dose level the individual variations were modest, a finding that is important for eventual clinical use of this potent drug.

Sodium thiosulfate fails to increase the therapeutic index of intravenously administered cis-diamminedichloroplatinum (II) in mice bearing murine and human tumors

SummaryIntravenous (i.v.) administration of sodium thiosulfate reduces the toxicity of cis-diamminedichloroplatinum (II) (CDDP). This effect, which allows the use of increased CDDP doses, has been exploited clinically in the intraperitoneal (i.p.) treatment of intraabdominal tumors. Recently, attempts have been made to treat extraperitoneal tumors by concurrent i.v. administration of CDDP and sodium thiosulfate. We have tested this approach in mice bearing systemic L1210 leukemia, s.c. growing Lewis lung carcinoma, C3H mammary carcinoma, and a human sarcoma growing in athymic nude mice. In all cases the antitumor activity of CDDP was substantially reduced in a manner dependent on the thiosulfate dose. Increased doses of CDDP, permitted by reduced toxicity in the presence of thiosulfate, raised the antitumor activity. However, the latter did not exceed that obtained by much lower doses in the absence of thiosulfate. The present experiments in animal models thus fail to support the clinical use of CDDP given i.v. together with its antidote, sodium thiosulfate.