Cytogenetic and antineoplastic effects by newly synthesised steroidal alkylators in lymphocytic leukaemia P388 cells in vivo.

New compounds with potential antitumour activity were synthesised by combining nitrogen mustard with the steroidal skeleton, in an effort to improve specificity and at the same time reduce systemic toxicity. The steroidal part is aimed to serve as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties. The purpose of the present investigation was to evaluate these compounds for anti-neoplastic activity. The compounds tested have as alkylators either para-NN-bis(2-chloroethyl)-aminophenyl-butyrate (CHL) or para-N,N-bis(2-chloroethyl)-aminophenyl-acetate (PHE) esterified with a differently modified steroidal nucleus. The eight newly synthesised compounds were compared on a molar basis with respect to their ability to induce sister chromatid exchanges (SCEs) and to modify proliferation rate indices (PRI) in lymphocytic leukaemia P388 cells in mice in vivo. The life span of BDF1 mice inoculated with P388 leukaemia cells was also estimated (anti-leukaemic activity). The compounds that were effective in inducing cytogenetic effects in lymphocytic leukaemia cells in vivo were also effective in inducing antineoplastic effects in BDF1 mice inoculated with P388 leukaemia cells. These results suggest that the in vivo cytogenetic effects in conjunction with the antineoplastic activity of modified steroidal alkylators depend on the configuration of the whole molecule and on the appropriate combination of the alkylator with the steroidal molecule: a pronounced cytogenetic and anti-neoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with either a steroidal nucleus that carries a cholesten group in the 17 position of the D-ring, or with a steroidal nucleus having an exocyclic NHCO-group in the D-ring. In contrast, a ketone group or an NHCO-group in the D-ring inserted endocyclically in the steroidal nucleus esterified with either CHL or PHE failed to induce cytogenetic or anti-neoplastic effects.

Cytoprotective activity of amifostine on cultured human lymphocytes exposed to irinotecan.

Irinotecan (camptothecin, CAM) is a topoisomerase-I inhibitor with a well established action in the chemotherapy of colorectal and ovarian cancer. Hematological and intestinal toxicity are commonly noted in patients treated with CAM. In this study, we examined the cytoprotective efficacy of amifostine (ethyol, ETH) against chromosomal damage induced by this drug on cultured peripheral human lymphocytes. Cultured lymphocytes were exposed to CAM (50 and 100 ng/ml of final concentrations) without or with ETH (in concentrations varying between 40 and 800 microg/ml of final culture volume). CAM's genotoxicity was quantified by counting the Sister Chromatid Exchange (SCEs) rate. The mitotic index (MI) and proliferation rate index (PRI) were also assessed. The SCE rate was increased following incubation with CAM, but the combined treatment of CAM with ETH significantly reduced the SCE formation, especially when ETH added at high concentrations. The MIs and PRIs remained also unaltered in cultures with CAM, but MIs were reduced with the combined treatment at high ETH concentrations. Clinical studies are required to assess the predicted benefits from ETH in patients receiving CAM.