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.
Subject(s)
Androstanes/pharmacology , Antineoplastic Agents/pharmacology , Azasteroids/pharmacology , Leukemia P388/drug therapy , Nitrogen Mustard Compounds/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Drug Synergism , Female , Humans , Lethal Dose 50 , Lymphocytes/drug effects , Male , Mice , Mice, Inbred BALB C , Mice, Inbred DBA , Sister Chromatid Exchange , Xenograft Model Antitumor AssaysABSTRACT
Recent studies have indicated that minor functional changes on the steroidal part of complex molecules, comprising of an alkylating moiety and a steroidal congener, lead to compounds with enhanced biological activity. The observed induction of the genotoxic, cytotoxic and antileukemic effects suggest a determinative role of the steroidal congener on the mechanism of action. In order to further elucidate the structural requirements responsible for this, we designed and synthesized a new modified steroid, carrying a 17beta-acetamide substituent and a B lactamic ring, and studied the ability of its esters with three potent nitrogen mustards to induce sister chromatid exchange (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro. The role of the steroidal skeleton was clearly stated by the results of the in vitro evaluation of the final compounds, as all three derivatives proved better inducers of SCE (58-102 SCE/cell) and cell division delays (1.18-1.25 PRI) than the simple nitrogen mustards (24-38 SCE/cell and 1.51-1.62 PRI). Obviously, the steroidal module enhances the formation of DNA adducts that cannot be repaired by excision repair enzymes probably through the induction of the interaction of these complex compounds with different base sequences or by disabling the repair mechanisms through the blockage of the enzymes responsible for excision repair. On the other hand, it seems that these compounds also act through a parallel site of action responsible for cell death when their primary binding site becomes saturated, as in higher concentrations two of the derivatives tested showed enhanced cytotoxicity while their ability to induce SCE stabilized.
Subject(s)
Drug Design , Esters/chemistry , Steroids/chemistry , Steroids/pharmacology , Alkylation , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Death , Cell Proliferation/drug effects , Cells, Cultured , DNA Adducts , DNA Repair , Esters/chemical synthesis , Esters/pharmacology , Humans , Lymphocytes/drug effects , Mechlorethamine/pharmacology , Mutagens/chemical synthesis , Mutagens/chemistry , Mutagens/pharmacology , Sister Chromatid Exchange/drug effects , Steroids/chemical synthesis , Structure-Activity RelationshipABSTRACT
7-keto-Delta(5)-steroids have been suggested for the treatment of several diseases. Their significant biological profile resulted in the development of a great number of methods and reagents for the allylic oxidation of Delta(5)-steroids. These methods and the biological evaluation of the main oxidized Delta(5)-steroids are summarized.
Subject(s)
Ketosteroids/chemical synthesis , Ketosteroids/metabolism , Cholesterol/chemical synthesis , Cholesterol/chemistry , Cholesterol/metabolism , Chromium/chemistry , Dehydroepiandrosterone/chemical synthesis , Dehydroepiandrosterone/chemistry , Dehydroepiandrosterone/metabolism , Humans , Ketosteroids/chemistry , Oxidation-Reduction , Oxygen/chemistry , tert-Butylhydroperoxide/chemistryABSTRACT
In order to increase the damaging effects on specific DNA sequences and decrease the subsequent toxicity, the use of homo-aza-steroidal esters of nitrogen mustards is already known. Two specific homo-aza-steroidal esters were mixed at different proportions and the resultant final mixtures were tested in vivo and in vitro. The effects of these on P388 and L1210 leukaemias, on SCE rates and on human lymphocyte proliferation kinetics were studied. The results demonstrate that the combined substances enhanced SCE induction (p < 0.05) and antitumour activity (p < 0.02) in a synergistic manner. A correlation was observed (p < 0.001) between the magnitude of the SCE response and the depression of the cell proliferation index.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Nitrogen Mustard Compounds/administration & dosage , Sister Chromatid Exchange/drug effects , Steroids/administration & dosage , Animals , DNA Damage , Female , Lethal Dose 50 , Leukemia L1210/genetics , Leukemia P388/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Nitrogen Mustard Compounds/toxicityABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Azasteroids/pharmacology , Nitrogen Mustard Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Female , Leukemia L1210 , Leukemia P388 , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Treatment OutcomeABSTRACT
The homo-aza-steroidal ester of p-bis (2-chloroethyl) amino phenylacetic acid (ASE) (I) the homo-aza-steroidal amide of p-bis (2-chloroethyl) amino phenylacetic acid (ASA) (II), and the parent compound p-bis (2-chloroethyl) amino phenylacetic acid (III) were tested in an effort to evaluate their ability to inhibit a transplanted leukemia (P388) in vivo, and the DNA synthesis of P388 cell cultures in vitro. The compounds' effects on Sister Chromatid Exchange (SCE) rate and on human cell proliferation kinetics in vitro were also studied. The above mentioned compounds were identified as displaying cytogenetic, cytostatic and antineoplastic effects, the ester compound being the more potent. The main conclusion from this study is that the existence of the esteric bond is necessary for the expression of the antitumor activity. The synthetic route for the preparation of the amidic derivative (II), as new product, is also reported.
