ABSTRACT
We have investigated the role of the allylic 7-ketone in oxidized Delta5-steroids on antileukemic activity. We synthesized and studied a series of oxidized and non-oxidized steroidal esters of p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), chlorambucil's active metabolite. In a comparative study of these 7-keto derivatives, on a molecular basis, regarding their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro, the results with these 7-keto derivatives, on a molecular basis, correlated well with their antileukemic potency against leukemia P388- and L1210-bearing mice, which proved to be significantly increased compared to that of the non-oxidized derivatives. Our results indicate that the role of the steroidal skeleton it is not only for the transportation of the alkylating agent into the cell, but also contributes directly to the mechanism of antileukemic action, by an as-yet unknown way. The main conclusion from this study is that the existence of the allylic 7-keto group in the skeleton of the Delta5-steroidal esters impressively enhances their antileukemic activity, while the toxicity remains at clinically acceptable levels, suggesting that this structural modification should be further investigated.
Subject(s)
Androstenes/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Ketones/chemical synthesis , Phenylacetates/chemical synthesis , Androstenes/chemistry , Androstenes/pharmacology , Animals , Cell Proliferation/drug effects , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Female , Ketones/chemistry , Ketones/pharmacology , Lethal Dose 50 , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Lymphocytes/cytology , Lymphocytes/drug effects , Lymphocytes/ultrastructure , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Phenylacetates/chemistry , Phenylacetates/pharmacology , Sister Chromatid Exchange , Structure-Activity RelationshipABSTRACT
Three newly synthesised steroidal esteric derivatives of nitrogen mustard (compounds 1-3) were comparatively studied on a molar basis regarding their ability to induce sister chromatid exchanges (SCEs) in normal human lymphocytes in vitro and therapeutic effects on leukemia P388 bearing mice. Compounds 1 and 3 are modified steroidal esters of p-methyl-m-N,N-bis(2-chloroethyl)amino benzoic acid, and compound 2 is a modified steroidal ester of chlorambucil. All compounds induced statistically significant increases in SCEs and decreases in proliferation rate indices (PRIs) of cultured human lymphocytes and significantly increased the life span of P388 bearing mice. In this study, the doses applied for therapeutic purposes upon leukemia P388 bearing mice in vivo were derived from cytogenetic observations in normal human lymphocytes in vitro. A substantially better therapeutic effect was obtained compared to the effect achieved after the use of quite higher doses related with LD(10) values. We have demonstrated that the order of anti-tumour effectiveness of the treatment schedules of the three newly synthesised compounds tested (at doses derived from cytogenetic observations) coincides with the order of the cytogenetic effects they induce. The SCE assay appears to have an application in the clinical prediction of tumour sensitivity to potential chemotherapeutics.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Drug Screening Assays, Antitumor/methods , Sister Chromatid Exchange/drug effects , Animals , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/chemistry , Female , Humans , In Vitro Techniques , Leukemia P388/drug therapy , Leukemia P388/genetics , Leukemia P388/pathology , Lymphocytes/drug effects , Male , Mice , Mice, Inbred DBA , Nitrogen Mustard Compounds/chemical synthesis , Nitrogen Mustard Compounds/chemistry , Nitrogen Mustard Compounds/pharmacology , Steroids/chemical synthesis , Steroids/chemistry , Steroids/pharmacologyABSTRACT
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.
