Enhanced Cytogenetic and Antineoplastic Effects by the Combined Action of Two Esteric Steroidal Derivatives of Nitrogen Mustards

Abstract

The authors studied the effect of two modified steroids containing different proportions (%) of alkylating agents alone or in combination on sister chromatid exchange (SCE) rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The two chemicals in mixtures enhance SCE induction and antitumor activity in a synergistic manner. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenyl acetic acid was found to be more effective than the homo-aza-steroidal ester of o-bis(2-chloroethyl)aminobenzoic acid in causing cytogenetic damage and antineoplastic activity. A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The order of the antitumor effectiveness of the five different treatments tested coincided with the order of the cytogenetic effects they induced.

Antileukemic and Cytogenetic Activity by Triple Administration of Three Modified Steroidal Derivatives of Nitrogen Mustards

“…Eight mice were used in the control groups, while each drug-treated group consisted of 6 mice; in each group, equal numbers of male and female mice were used. [ 19,20] in both in vitro and in vivo experiments, no similar results were obtained in the present study; however, surprisingly, an equivalently potent but almost nontoxic mixture (AMO-5) was observed. Although synergy was achieved in the in vitro experiments for AMO-2 and AMO-3 and cures were obtained by three of the fi ve mixtures tested in the in vivo tests, the fi nal oncostatic and antileukemic activity of the triple administration needs much more investigation.…”

“…Mixture AMO-5 proved the most potent against leukemia P388 (T/C% = 294, and 1 cure out of 6 was recorded), while at the same time, it proved less toxic ( table 3 ). No synergistic effects were observed in these in vivo experiments, in contrast to the clear synergism, which was recorded using the combinations ASE/MSE and ASE/OSE [19,20] .…”

“…These evidences have prompted us to study the in vitro and in vivo antileukemic effi cacy of the combined administration of two couples of esteric steroidal derivatives with different nitrogen mustards in different proportions of the mixture [19,20] . Those were 3 ␤ -hydroxy-17 ␣ -aza-D -homo-5 ␣ -androstan-17-one p -N,N-bis(2-chloroethyl)-amino phenyl acetate (ASE) in combination with 3 ␤ -hydroxy-17 ␣ -aza-D -homo-5 ␣ -androstan-17-one p -methylm -N,N-bis(2-chloroethyl)aminobenzoate (MSE) and ASE with 3 ␤ -hydroxy-17 ␣ -aza-D -homo-5 ␣ -androstan-17-one o -N,N-bis(2-chloroethyl)amino benzoate (OSE), respectively ( fi g. 1 ).…”

Evaluation and characterization of micronuclei induced by the antitumour agent ASE [3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)amino phenylacetate] in human lymphocyte cultures

“…with previously published findings showing that ASE induces chromosome abnormalities and sister chromatid Also, support was found that MN frequencies vary with culture time (56, 72, 80 and 92 h) and this was exchange in CHO cells (Athanasiou et al, 1983) as well sister chromatid exchange and cytotoxic effects in human attributed to second division binucleate cells. Comparing the percentage of multinucleated (tri-and tetranucleated) cells in lymphocytes (Mourelatos et al, 1987;Nikolaropoulos et al, 1997;Papageorgiou et al, 1999). ASE is an alkylating comcontrol cultures between 56 and 72 h, it was found that 20-30% of the cells were multinucleated at the second sampling pound and its genetic activity is mediated through DNA alkylation, although the specific DNA lesions induced by this time.…”

“…In the (Papageorgiou et al, 1999). It is noteworthy that although present study an effort has been made to evaluate the ASE exerts about the same antineoplastic activity as ability of ASE to induce micronuclei (MN) in human chlorambucil, it is less toxic with a more prolonged action lymphocytes treated in vitro using the cytokinesis-block (Stevenson and Patel, 1973; Catsoulacos et al, 1978).…”