Toxicity of dolastatin 10 in mice, rats and dogs and its clinical relevance

Purpose: Dolastatin 10 (DOL 10), an oligopeptide isolated from the sea hare Dolabella auricularia, has been shown to be a highly potent cytotoxic agen t in a variety of human tumor cell lines. The purpose of this study was to conduct preclinical toxicity evaluations to determine the target organ(s) o f toxicity and its reversibility, the dose-limiting toxicity and the maximu m tolerated dose (MTD), and to use this information for arriving at a safe starting dose and dose schedule for phase I clinical trails. Methods: DOL10 was administered as a single intravenous bolus dose to CD2F1 mice, Fischer -344 rats and beagle dogs. Endpoints evaluated included clinical observatio ns, body weights, hematology, serum clinical chemistry, and microscopic pat hology of tissues. Results: The MTD (i.e. the highest dose that did not cau se lethality but produced substantial toxicity) was approximately 1350 mu g /m(2) body surface area (450 mu g/kg) in mice, 450 mu g/m2 (75 mu g/kg) in rats and less than or equal to 400 mu g/m(2) (less than or equal to 20 mu g /kg) in dogs. Adverse signs were observed at doses greater than or equal to 1350 mu g/m(2) in mice, greater than or equal to 150 mu g/m(2) in rats and greater than or equal to 400 mu g/m(2) in dogs. Decreased weight gain or a ctual weight loss was observed at doses greater than or equal to 1350 mu g/ m(2) in mice, greater than or equal to 600 mu g/m(2) in rats and greater th an or equal to 450 mu g/m(2) in dogs. In all three species, the primary tar get organ of toxicity was the bone marrow, as indicated by decreases in the numbers of erythroid cells, myeloid cells, and megakaryocytes in the femor al bone marrow and by decreased white blood cell (WBC) and reticulocyte cou nts in peripheral blood. Marked neutropenia (i.e. >50% decrease compared to control animal or baseline values) was the principal effect on WBCs and oc curred within a week of dosing. A mild anemia was evident I week after admi nistering the drug to rats and dogs. The hematologic effects were transient and reversed by study termination. Other lesions at the MTD levels were ce llular depletion and necrosis in lymphoid organs (rats and dogs), marked de pletion of extramedullary hematopoietic cellular elements in the spleen (ra ts), thymic atrophy (mice and dogs), and minimal cellular necrosis in the i leum (rats). More extensive and severe pathology was observed in animals sa crificed in a moribund condition or found dead. Conclusions: Myelotoxicity was dose-limiting in all three species with mice being the least sensitive. In a phase I clinical trial, granulocytopenia was dose-limiting. Moreover, the MTD of DOL10 for rats and dogs is comparable to the human MTD. Therefo re, the results from the preclinical toxicology studies correctly predicted a safe starting dose, the dose-limiting toxicity, and the MTD in humans.