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
We investigated the effects of two newly synthesized steroidal derivatives of nitrogen mustard on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The compound 33-hydroxy-5alpha,22alpha-spirostan- 12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(1) was, on a molar basis, less effective in inducing sister chromatid exchange and suppressing cell proliferation rate indices than compound 3beta-hydroxy-12alpha-aza-C-homo-5alpha,22alpha-spirostan-12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(2). A correlation was observed between the magnitude of the sister chromatid exchange response and the depression of cell proliferation index. We also studied the effects of the aforementioned compounds on Lewis lung carcinoma. The order of the percent inhibition of tumor growth achieved by the compounds coincides with the order of the cytogenetic effects they induce.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Animales , Antineoplásicos Alquilantes/química , Carcinoma Pulmonar de Lewis/prevención & control , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Compuestos de Mostaza Nitrogenada/química , Intercambio de Cromátides HermanasRESUMEN
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.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/administración & dosificación , Intercambio de Cromátides Hermanas/efectos de los fármacos , Esteroides/administración & dosificación , Animales , Daño del ADN , Femenino , Dosificación Letal Mediana , Leucemia L1210/genética , Leucemia P388/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Compuestos de Mostaza Nitrogenada/toxicidadRESUMEN
Enhanced sister chromatid exchange (SCE) frequency by either melphalan (Mel) or epirubicin (Epir) was observed when human lymphocytes were exposed in vitro to 9-nitro-20(S)-camptothecin (9NC). A correlation was observed between the magnitude of the SCE response and the depression of the cell proliferation index. The antitumor activity of Mel and of 9NC was tested on leukemia P-388-bearing mice. The two chemicals in combination enhance antitumor activity in a synergistic manner. Therefore, the in vivo antitumor effect of Mel in conjunction with 9NC appears to correlate well with the in vitro synergistic effect on SCE induction caused by the combined Mel plus 9NC treatment. Teratogenesis Carcinog. Mutagen. 20:141-146, 2000.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/análogos & derivados , Epirrubicina/farmacología , Leucemia P388/tratamiento farmacológico , Linfocitos/efectos de los fármacos , Melfalán/farmacología , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/farmacología , Camptotecina/uso terapéutico , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Epirrubicina/administración & dosificación , Epirrubicina/uso terapéutico , Humanos , Linfocitos/ultraestructura , Melfalán/administración & dosificación , Melfalán/uso terapéutico , RatonesRESUMEN
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.