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

Abstract

Combination chemotherapy is widely and routinely used for most cancer patients. The main objective of this study is an effort to develop new anticancer drugs and procedures with enhanced antitumor activity and reduced toxicity. This study was designed to determine the antileukemic and cytogenetic activity of five mixtures of three specific steroidal esters of aromatic nitrogen mustards in different proportions. This is the next step of two previous studies where the combination of two such esteric analogues was investigated with promising results. All of the five mixtures used proved active against leukemia P388 and in the induction of sister chromatid exchanges, indicating that the combination of the same class of compounds can be successful, especially when a highly potent agent is combined with another less active but probably mechanistically supplementary one. These results can be used in future experiments in order to further scout the specific role of the steroidal part of these molecules in the antileukemic potency of them.

Cytogenetic and Antineoplastic Effects of Modified Steroidal Alkylators

“…The SCE assay in vitro has been established as a highly predictive method for the clinical behavior for drugs for which a correlation between cell killing and induction of SCEs has been established, as it seems applicable for compound 4. It has been reported from earlier studies that both the chemical structure of the nitrogen mustard and the configuration of the steroidal moiety determine the antineoplastic effect of these compounds (Papageorgiou et al, 2005;Fousteris et al, 2007;Karayianni et al, 2003).…”

“…In an effort to extend previous observations on the genotoxic effects of newly synthesized compounds (Papageorgiou et al, 2005;Fousteris et al, 2007), we investigated in this study the cytogenetic and antileukemic effects of four different newly synthesized compounds that contain CHL and PHE as alkylating agents and are also conjugated with steroidal ester modified in the B and D steroidal rings.…”

“…The most active compound 4 presented a dose-dependent, statistically significant increase of SCEs as compared to compounds 1, 2, and 3. Compound 4 has been proved to be cytogenetically active, while it seems that the modifications in the steroidal skeleton have an important role in the activity of the compounds (Papageorgiou et al, 2005;Fousteris et al, 2007).…”

“…In a previous study, we have shown that minor functional changes in the B steroidal ring (e.g., 7-keto-group) of a steroidal ester (androstan) had considerable effects on the molecule's antileukemic, genotoxic, and cytotoxic activity, leading us to assume that this modification is fundamental to the design of more effective molecules (Fousteris et al, 2007).…”

The cytogenetic action of ifosfamide, mesna, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study

“…It is this property that classifies IFO among agents that should only be administered with great attention and precision with respect to the dosage, and it is for this reason that special software programs have been developed for its administration (Okayasu et al 2009). IFO and its derivatives, along with other alkylating factors are well known for inducing SCEs (Ciesielska et al 1993;Fousteris et al 2007;Karapidaki et al 2009;Digkas et al 2010;Mourelatos et al 2012a).…”