Effects of L-2-oxothiazolidine-4-carboxylate on the cytotoxic activity andtoxicity of cyclophosphamide in mice bearing B16F10 melanoma liver metastases

Glutathione (GSH) is the major non-protein thiol in cells that plays a crit ical role against damage from electrophilic agents such as alkylating drugs . Selective therapeutic GSH elevation in normal but not in tumour cells has been suggested as a means of protecting host tissues against more intense doses of chemotherapy. The present study investigated the response of B16 m elanoma to treatment with the cysteine pro-drug L-2-oxothlazolidine-4-carbo xylate (OTZ), alone and in combination with cyclophosphamide (CY). We found that OTZ decreased the GSH levels and proliferation rate of B16 melanoma c ells in vitro, sensitizing them to the cytotoxic action of the activated me tabolite of CY, acrolein (AC). In contrast to OTZ, the cysteine deliverer N -acetylcysteine (NAC) enhanced B16 melanoma cell proliferation by increasin g GSH levels, and markedly decreased the sensitivity of these tumour cells to AC. In vivo studies showed the antitumoral activity of OTZ in B16 melano ma liver metastasis-induced mice, increasing their life span. We also obser ved that, whereas with CY treatment the GSH levels in peripheral blood mono nuclear cells (PBMCs) were reduced and a dose-dependent leukopenia was prod uced, OTZ significantly increased PBMC GSH content, reducing toxicity and e nhancing the survival of mice bearing established melanoma liver metastases treated with lethal dose CY. These results suggest a critical role for OTZ In protecting against alkylator agent-induced immunosuppression, which may allow the dose escalation of these cytostatic drugs to improve their thera peutic benefit in the treatment of malignant melanoma. (C) 2000 Lippincott Williams & Wilkins.