RESUMEN
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.
Asunto(s)
Androstanos/farmacología , Antineoplásicos/farmacología , Azaesteroides/farmacología , Leucemia P388/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Sinergismo Farmacológico , Femenino , Humanos , Dosificación Letal Mediana , Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Intercambio de Cromátides Hermanas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Ésteres/química , Esteroides/química , Esteroides/farmacología , Alquilación , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Muerte Celular , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Aductos de ADN , Reparación del ADN , Ésteres/síntesis química , Ésteres/farmacología , Humanos , Linfocitos/efectos de los fármacos , Mecloretamina/farmacología , Mutágenos/síntesis química , Mutágenos/química , Mutágenos/farmacología , Intercambio de Cromátides Hermanas/efectos de los fármacos , Esteroides/síntesis química , Relación Estructura-ActividadRESUMEN
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.