Toxicological testing of cytotoxic drugs (review).

Cytotoxic drugs are a unique therapeutic class of fundamental importance in current antineoplastic chemotherapy. These drugs belong to many chemical and chemotherapeutic classes. They are cytotoxic by design and are able to cause serious dose-limiting adverse effects at therapeutic doses. Most antineoplastic dosing strategies focus on minimizing cytotoxicity rather than optimizing efficacy. In turn, cytotoxicity is interconnected with other therapeutic considerations, including cell status (renewing vs. non-renewing cell types), cell membrane transport integrity, intracellular activation status, immune system integrity, cellular repair status, and drug resistance. Regulatory requirements for the development of cytotoxic drugs are not well characterized, and differences exist in regional requirements. A safety assessment package which is utilized and accepted world-wide does not yet exist, despite many efforts of harmonization. In this report, the authors introduce a comprehensive safety assessment package for cytotoxic drugs, based on institutional experience acquired globally with this class of drugs, that fulfills both scientific and world-wide regulatory requirements for this very important therapeutic category.

Successful treatment of autoimmunity in MRL/1 mice with LS-2616, a new immunomodulator.

Autoimmune MRL/1 mice were treated with a recently developed substance with immunomodulating properties, LS-2616. Treatment was initiated at the age of 8 weeks, before the onset of clinically apparent disease, and at 16 weeks of age, after development of established lupus disease. Beneficial therapeutic effects were obtained, even when LS-2616 was administered at the lowest dose tested (1 mg/mouse/week) to 16-week-old mice. The effects of LS-2616 on longevity, as well as on development of lymphadenopathy, splenomegaly, glomerulonephritis, and vasculitis, were pronounced and were comparable with those of cyclophosphamide. The results obtained suggest a potential role for LS-2616 in the treatment of autoimmune disease in humans.

Mammary tumour inhibition and subacute toxicity in rats of prednimustine and of its molecular components chlorambucil and prednisolone.

Prednimustine, a chlorambucil ester of pregnisolone, retarded growth of DMBA-induced mammary tumours in rats and reduced the number of tumours. A combination of chlorambucil and prednisolone (C + P) in the same proportion as in prednimustine, had similar effects, 8 and 26 mg per kg of the C + P combination being equipotnet to 16 and 64 mg per kg of prednimustine, respectively. The mortality figures suggested that prednimustine was considerably less toxic than equipotent doses of C + P. This toxicity difference was confirmed in a parallel investigation of the subacute toxicity in rats of prednimustine and C + P. This study showed that the mortality, reduction of lymphocytes and platelets, and bone marrow depression was much lower after pregnimustine than after equimolar amounts of the C + P combination. The results suggest that the low toxicity of prednimustine makes this drug a better cytostatic agent than the C + P combination treatment.