Genotoxic, cytostatic, antineoplastic and apoptotic effects of newly synthesized antitumour steroidal esters.

In this study, we have investigated the genotoxic, cytostatic, antineoplastic and apoptotic effects of three newly synthesized modified steroidal esters, having as alkylating agent p-N,N-bis(2-chloroethyl) aminophenyl butyrate (CHL) or p-N,N-bis(2-chloroethyl) aminophenyl acetate (PHE) esterified with the steroidal nucleus modified in the B- and D-ring. The genotoxic and cytotoxic effects of the compounds were investigated both in vitro, in lymphocyte cultures obtained from blood samples of healthy donors and in vivo, in ascites cells of P388 leukemia obtained from the peritoneal cavity of DBA/2 mice. Preparations were scored for sister-chromatid exchange (SCE) and proliferation-rate indices (PRI).

Synthesis, characterization, toxicity, cytogenetic and in vivo antitumor studies of 1,1-dithiolate Cu(II) complexes with di-, tri-, tetra- amines and 1,3-thiazoles. Structure-activity correlation.

A series of new mixed-ligand neutral copper(II) complexes of the general type [Cu(amine)(i-MNT)] and [Cu(tz)(i-MNT)] was prepared and characterized by elemental, spectroscopic methods, mu(eff), Lambda(mu) measurements and molecular modeling studies. The acute toxicity, the cytogenetic and the in vivo antitumor activity of the new complexes, is related to their chemical and physicochemical properties. Among the Cu(II) compounds tested the complex with 2-amino-5-methyl thiazole increases significantly the life span of leukemia P388 bearing mice in vivo.

Genotoxic and cytotoxic effects of different types of dental cement on normal cultured human lymphocytes.

In this study we have investigated the genotoxic and cytotoxic effects of eluates derived from different types of commercially available dental cements, including glass ionomer cements (GICs) (Ketac Cem/3M ESPE and GC Fuji I/GC Corp), resin-modified glass ionomer cements (RM-GICs) (RelyX Luting/3M ESPE and Vitrebond/3M ESPE) and dual-cure resin cements (RCs) (Variolink II/ Ivoclar-Vivadent and Panavia F 2.0/Kuraray) on normal cultured human lymphocytes. Lymphocyte primary cultures obtained from blood samples of three healthy donors were exposed to serial dilutions of eluates derived from specimens of each material tested.

Sister-chromatid exchange, chromosomal aberrations and delays in cell-cycle kinetics in human lymphocytes induced by dental composite resin eluates.

We have investigated eluates derived from commercially available composite resin-based materials used for direct (Tetric Ceram/Ivoclar-Vivadent, Simile/Pentron, Filtek Z-250/3M ESPE) and indirect (Adoro/Ivoclar-Vivadent and Conquest Sculpture/Pentron) dental restorations, with respect to their genotoxic effects on human peripheral lymphocytes. Primary lymphocyte cultures obtained from blood samples of three healthy donors were exposed to eluates of freshly cured specimens of all the materials tested. Metaphases were induced with phytohaemagglutinin, collected after a 72-h treatment using colchicine and stained with the Fluorescence Plus Giemsa (FPG) procedure.

Synthesis and cytogenetic studies of structure--biological activity relationship of esters of Hecogenin and aza-homo-Hecogenin with N,N-bis(2-chloroethyl)aminocinnamic acid isomers.

The esters of Hecogenin and aza-homo-Hecogenin with N,N-bis(2-chloroethyl)aminocinnamic acid isomers have been prepared and their cytogenetic studies of structure-biological activity relationship were evaluated. The cytogenetic effects (sister chromatid exchanges (SCEs) induction and proliferation rate indices (PRIs) depression) by o-, m- and p-[N,N-bis(2-chloroethyl)amino] cinnamic acid were also investigated. Among the above compounds tested, those of the m-[N,N-bis(2-chloroethyl)amino] cinnamic acid and of the o-[N,N-bis(2-chloroethyl)amino] cinnamic acid ester of aza-homo-Hecogenin were more active in comparison to the others.

The allylic 7-ketone at the steroidal skeleton is crucial for the antileukemic potency of chlorambucil's active metabolite steroidal esters.

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.

A new approach for evaluating in vivo anti-leukemic activity using the SCE assay. An application on three newly synthesised anti-tumour steroidal esters.

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.

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

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.

Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid.

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice.

Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects.

The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2] x H2O and [Pd(AcTsc)2] while the rest, i.

Antineoplastic and cytogenetic effects of platinum(II) and palladium(II) complexes with pyridine-2-carboxyaldehyde-thiosemicarbazone.

The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)2] and [Pt(PyTsc)2].

Antineoplastic and cytogenetic effects of complexes of Pd (II) with 4N-substituted derivatives of 2-acetyl-pyridine-thiosemicarbazone.

The effect of novel Pd(II) complexes with derivatives of 2-acetyl-pyridinethisemicarbazone, N4-ethyl (HAc4Et) and 3-hexamethyleneiminylthiosemicarbazone (HAchexim), on Sister Chromatid Exchange (SCE) rates and human lymphocyte proliferation kinetics was studied. Also, the effect of Pd(II) complexes on DNA synthesis of P388 and L1210 cell cultures and against Leukemia P388 was investigated. Among these compounds, the compound Bis(3-hexamethyleneiminyl-2-acetylpyridine-thisemicarbazonato++ +) palladium (II) was found to be distinctly effective against Leukemia P388, in inhibiting incorporation of 3H-thymidine into DNA and in inducing SCEs and cell division delays.

Enhancement of cytogenetic damage and of antineoplastic effect in lymphoid L1210 leukemia cells treated with prostaglandin E2 and cyclophosphamide in vivo.

An enhanced frequency of sister-chromatid exchanges (SCEs) and increased cell division delays induced by cyclophosphamide (CP) were observed when lymphoid L1210 leukemia cells were post-treated in vivo with prostaglandin E2 (PGE2). CP gave a slight, non-significant increase in survival while PGE2 gave a slight, non-significant decrease in survival. However, PGE2 in combination with CP was found to have a non-significant potentiating effect on survival in comparison with mice treated with CP alone.

Comparison of current alkylating agents with a homo-aza-steroidal ester for antineoplastic activity.

The modified steroidal alkylating agent, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-bis(2-chloroethyl)aminophenoxyacetate++ + has been tested against L1210 and P388 leukemias, and Lewis lung cancer, on DNA synthesis of EAT, L1210, P388, and BHK cell cultures, and on the induction of sister chromatid exchange. Comparable studies in vivo and in vitro were also done with p-bis(2-chloroethyl)aminophenoxyacetic acid, cyclophosphamide, melphalan, and chlorambucil.

Enhancement of antineoplastic effect and attenuation of sister chromatid exchanges by prostaglandin E2 in Ehrlich ascites tumour cells treated with cyclophosphamide in vivo.

Reduced sister chromatid exchanges (SCE) frequency in response to cyclophosphamide (CP) was observed when Ehrlich ascites tumour (EAT) cells were exposed in vivo to 2 micrograms/g body weight of prostaglandin E2 (PGE2). 1 h before i.p.

Effects of alkylating antineoplastics alone or in combination with 3-aminobenzamide on genotoxicity, antitumor activity, and NAD levels in human lymphocytes in vitro and on Ehrlich ascites tumor cells in vivo.

Enhanced cytogenetic damage by the homo-aza-steroidal ester of p-bis(2-chloroethyl)-aminophenylacetic acid (ASE) was observed when human lymphocytes in vitro or Ehrlich ascites tumor (EAT) cells in vivo were exposed to nontoxic concentrations of 3-amino-benzamide (3-AB). 3-AB at these concentrations was found to enhance synergistically the cytogenetic damage induced in vivo by cyclophosphamide (CP), a metabolically activated chemotherapeutic, or chlorambucil (CBC) in EAT cells. One hour before i.