7-Keto hybrid steroidal esters of nitrogen mustard: cytogenetic and antineoplastic effects.

Abstract

Four newly synthesized antitumor steroidal compounds were compared, on a molar basis, regarding their ability to induce sister chromatid exchanges (SCEs) and cell division delays. The concept of designing and developing these compounds (1-4) is to enhance the anticancer activity of esteric steroidal derivatives of nitrogen mustard by introduction of a keto group at the 7-position of the D5 steroidal skeleton, and a double bond between positions 6 and 7 of the B ring of the steroidal nucleus. In our study, the cytogenetic and antileukemic effects of these newly synthesized compounds are reported. The four substances induced statistically significant enhancement of SCEs and of cell division delays, and in both schedules used, therapeutic effects. However, compounds 1 and 3 showed increased genotoxicity towards human lymphocytes (p<0.001) and antileukemic activity towards P388 leukemias (p<0.001), compared to compounds 2 and 4. It seems that the introduction of a keto group at the 7-position of the steroidal skeleton enhances the antitumor effect of these substances in comparison with our previous studies with the corresponding compounds characterized by the absence of the 7-keto group. Therefore, the in vivo antitumor effect of the four compounds appears to correlate well with the in vitro cytogenetic effect caused by these chemicals.