RESUMEN
The modified steroidal alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam [p-[bis(2-chloroethyl)amino]phenyl]acetate (NSC 290205) is active in treating the LX-1 lung and MX-1 breast xenografts as well as a number of rodent tumors. Of 13 tumors tested, activity has been shown in 10 systems. Two systems have not received adequate testing and negative results were recorded in 1 system.
Asunto(s)
Antineoplásicos/uso terapéutico , Azaesteroides , Neoplasias/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular , Neoplasias del Colon/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Humanos , Leucemia Experimental/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Ratones , Trasplante de NeoplasiasRESUMEN
The homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenoxy] acetic acid, 3 beta-hydroxy 13 alpha - amino - 13,17 - seco - 5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenoxyacetate, gave a 100% increase in lifespan over controls in the treatment of L1210 leukemia by IP administration on a days 1 and 4 treatment schedule. This ester gave a maximum activity of 383% increased lifespan over controls in the treatment of P388 leukemia by IP administration on a daily treatment schedule. Activity in advanced L1210 (41% increased lifespan) and P388 leukemias (173% increased lifespan) was maintained, indicating that this compound is the most promising of a number of congeners tested to date.
Asunto(s)
Alquilantes/uso terapéutico , Azaesteroides/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Esteroides Heterocíclicos/uso terapéutico , Animales , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Ratones , Ratones Endogámicos , Factores de TiempoRESUMEN
Three new modified steroidal alkylating agents, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl)aminophenylacetate, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis-(2-chloroethyl)aminophenylbutyrate, and 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenylacetate are active in treatment of L1210 and P388 leukemias. A stereoisomer of the first compound, 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)aminophenylacetate, was tested in L1210 leukemia. This stereoisomer, in which the alkylating agent is linked to the modified steroid in the axial position, is active only as much higher doses in L1210 leukemia. The results of testing these compounds and previous results from similar compounds allow certain conclusions to be drawn regarding structure-activity relationships. The presence of the lactam moiety is the major structural feature that confers activity in the murine leukemias. The steric arrangement of the alkylating moiety at position 3 and the hydrogen atom at position 5 influence toxicity and antileukemic activity.
Asunto(s)
Antineoplásicos/uso terapéutico , Lactamas/uso terapéutico , Leucemia Experimental/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Animales , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Femenino , Ratones , Ratones Endogámicos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
For the rational design of more specific alkylating agents, we suggested new biological platforms able to deliver the alkylating moieties to specific target site and on the other hand we hoped to lead in compounds with synergistic activity. As biological platforms have been used steroidal lactams of A and D- ring and as alkylating agents carboxylic derivatives of N,N-bis (2-Chloroethyl) aniline which combine to the steroid by an easily cleaved ester bond. These homo-aza-steroidal esters gave satisfactory results in early and advanced P388, L1210 leukemias and solid tumors. Whereas unmodified steroidal esters have generally been reported to be inactive in treatment of L1210 leukemia. The steric arrangement of the alkylating moiety greatly effects toxicity and activity of the drugs, while the steric arrangement of the hydrogen atom at position 5 influences these parameters. Isosterism of alkylating agent is the factor for biological action. The amide group of the lactam molecule may be essential for activity.
Asunto(s)
Alquilantes/farmacología , Mostaza de Anilina/análogos & derivados , Antineoplásicos/farmacología , Diseño de Fármacos , Lactamas/farmacología , Alquilantes/química , Mostaza de Anilina/química , Mostaza de Anilina/farmacología , Animales , Antineoplásicos/química , Lactamas/química , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The homo-aza-steroidal esters of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline are reviewed. In particular, we discuss the antitumor activity of the esters of homo-aza steroids in which the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid is linked to the C-3 or C-17 position, while the lactam nucleus is linked to the D or A ring of the modified steroid respectively. The current literature indicates clearly that the potential of these esters is due to the synergistic activity of both the lactam and the p-N,N-bis(2-chloroethyl)aminophenoxyacetic acid.
Asunto(s)
Antineoplásicos/uso terapéutico , Azaesteroides , Neoplasias del Colon/tratamiento farmacológico , Homoesteroides/uso terapéutico , Leucemia L1210/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Fenoxiacetatos/uso terapéutico , Esteroides , Animales , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The homo-aza-steroidal esters of conjugated carboxylic derivatives of nitrogen mustards are reviewed. Particularly we discuss the antitumor activity of cinnamic acid and benzoic acid mustard isomers, esters of homo-aza-steroids in which the mustard acid is linked to the C-3 or C17 position, while the lactam nucleus is in the D or A ring of the steroid respectively. The current literature indicates that the potential is due to the synergistic activity of both the steroidal lactam and the mustard of the acids. Steroidal lactams, namely 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam, the isomer 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic- 13,17-lactam, 3 beta-hydroxy-13 alpha-amino 13,17-seco-5-androsten-17-oic-13,17-lactam and the 17 beta-hydroxy-3-aza-A-homo- 4 alpha-androsten-4-one, have been used as biological platforms of the cinnamic acid, of the benzoic acid mustard isomers and the 4-methyl-benzoic acid mustard. The twelve esters of cinnamic acid mustard isomers were tested against P388, L1210 leukemias Ehrlich ascites tumor (EAT) and melanoma B16 in vivo. The effect of homo-aza-steroidal esters of N,N-bis(2-chloroethyl) amino cinnamic acid isomers on the incorporation of the radioactive precursors into DNA, RNA and proteins of L1210, P388 leukemias, Ehrlich ascites tumor (EAT) and Baby Hamster Kidney (BHK) cells, was investigated. The effect of the homo-aza-steroidal esters of N,N-bis(2-chloroethyl) aminobenzoic acid isomers on the incorporation of radioactive precursors into DNA, RNA and proteins was studied in L1210, P388 leukemias, Ehrlich ascites tumor and Baby hamster kidney cells.
Asunto(s)
Antineoplásicos/uso terapéutico , Azaesteroides/uso terapéutico , Homoesteroides/uso terapéutico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Animales , Antineoplásicos/toxicidad , Azaesteroides/química , Azaesteroides/toxicidad , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cricetinae , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/efectos de los fármacos , Homoesteroides/química , Homoesteroides/toxicidad , Riñón , Leucemia L1210/tratamiento farmacológico , Leucemia L1210/metabolismo , Leucemia P388/tratamiento farmacológico , Leucemia P388/metabolismo , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Estructura Molecular , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/efectos de los fármacos , Compuestos de Mostaza Nitrogenada/química , Compuestos de Mostaza Nitrogenada/toxicidad , ARN Neoplásico/biosíntesis , ARN Neoplásico/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
7 alpha-, 17 alpha-Diaza-7, 17-dioxo-B, D-dihomo-5-androsten 3 beta-p-N, N-bis (2- chloroethyl)aminophenylacetate, a modified steroidal alkylating agent, is active in the treatment of P388 and L1210 leukemias in vivo. The compound was also tested in vitro against L1210 and P388 leukemias, on DNA, RNA and protein synthesis and showed high inhibition effect. Also increases the frequency of Sister Chromatid Exchanges and reduces the replication index of human lymphocytes.
Asunto(s)
Antineoplásicos/toxicidad , Antineoplásicos/uso terapéutico , Compuestos Aza/toxicidad , Compuestos Aza/uso terapéutico , Azaesteroides , Homoesteroides/toxicidad , Homoesteroides/uso terapéutico , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Intercambio de Cromátides Hermanas/efectos de los fármacos , Animales , Compuestos Aza/síntesis química , División Celular/efectos de los fármacos , Células Cultivadas , Femenino , Homoesteroides/síntesis química , Humanos , Indicadores y Reactivos , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBA , Ratones Endogámicos , Estructura Molecular , Células Tumorales CultivadasRESUMEN
The p-[N,N-bis (2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane have been prepared and their antitumor activity evaluated against L1210 leukemia, P388 leukemia, Ehrlich ascites tumor (EAT) and Lewis Lung Carcinoma (LLC). The results are compared with those of the p-[N,N-bis (2-chloroethyl)amino]phenylacetate of 3 beta-hydroxy-17 alpha-aza-D-homo- 5 alpha-androstan-17-one. The above compounds were also tested in vitro against L1210, P 388, EAT and BHX cell cultures. All compounds were found to be active and their structure-activity relationship is discussed.
Asunto(s)
Androstanos/farmacología , Antineoplásicos/farmacología , Azaesteroides/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Leucemia L1210/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/farmacología , Androstanos/síntesis química , Androstanos/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Azaesteroides/síntesis química , Azaesteroides/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Compuestos de Mostaza Nitrogenada/síntesis química , Compuestos de Mostaza Nitrogenada/uso terapéutico , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Methyl 2-bromoacetyl-4,5-dimethoxyphenylacetate was prepared by reacting cupric bromide with methyl 2-acetyl-4,5-dimethoxyphenylacetate. Aminoacetyl derivatives formed on condensation of substituted p-aminobenzoic esters with the bromoacetyl derivative. Some prepared compounds were tested for local anesthetic and anti-inflammatory activities.
Asunto(s)
Fenilacetatos/síntesis química , Aminobenzoatos , Ácidos Aminosalicílicos , Anestésicos Locales/farmacología , Animales , Antiinflamatorios/farmacología , Fenómenos Químicos , Química , Córnea/efectos de los fármacos , Cobayas , Fenilacetatos/farmacologíaRESUMEN
3beta-Hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam 4-[p[bis(2chloroethyl)amino]phenyl]butyrate was prepared by reacting 4-[p-[bis(2-chloroethyl)amino]phenyl]butyryl chloride hydrochloride with 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17-lactam. They cytostatic action of the ester was investigated on two tumor systems (B16 melanoma on C57 b1 mice and T8-Guerin on rats).
Asunto(s)
Antineoplásicos , Clorambucilo/análogos & derivados , Animales , Antineoplásicos/uso terapéutico , Clorambucilo/farmacología , Clorambucilo/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/tratamiento farmacológico , RatasRESUMEN
Four steroidal lactams of the A- and D-rings were used for the esterification in the C-3 or C-17 positions, respectively, of their nuclei with the N,N-bis(2-chloroethyl)aminocinnamic acid isomers. The condensation reaction of the hydroxylic group of the steroidal lactams with each mustard was effected in dichloromethane in the presence of the catalyst p-dimethylaminopyridine and dicyclohexylcarbodiimide as dehydrating agent. The esters were obtained in pure form after column chromatography, and their structures were verified and confirmed by analytical methods (IR and UV spectra). The 12 esters were tested in vivo against P388, L1210 leukemias, Ehrlich ascites tumor, and melanoma B16. The esters 3 alpha-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17- oic-13,17-lactam-o,m,p-N,N-bis(2-chloroethyl)aminocinnamates, in which the alkylating agents are linked to the modified steroid in the axial position, are inactive in the above experimental animal tumor systems. The effect of the homo-aza-steroidal esters of N,N-bis(2-chloroethyl)aminocinnamic acid isomers on the incorporation of radioactive precursors into DNA, RNA, and proteins of L1210, P388 leukemias, Ehrlich ascites tumor, and baby hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursors was obtained with the ortho-derivatives, yielding > 40% inhibition of thymidine incorporation in all tumor lines tested. The effect of four esters in which the m- N,N-bis(2-chloroethyl)aminocinnamic acid is linked to the modified steroids on sister chromatid exchanges in human lymphocyte culture was investigated.
Asunto(s)
Antineoplásicos/síntesis química , Azaesteroides/síntesis química , Cinamatos/síntesis química , Mutágenos/síntesis química , Alquilantes/síntesis química , Alquilantes/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Azaesteroides/farmacología , Azaesteroides/toxicidad , Fenómenos Químicos , Química Física , Cinamatos/farmacología , Cinamatos/toxicidad , Femenino , Leucina/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Mutágenos/farmacología , Mutágenos/toxicidad , Intercambio de Cromátides Hermanas/efectos de los fármacos , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Timidina/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos , Uridina/metabolismoRESUMEN
The effect of P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-N-methyl-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 3) and 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstane (compound 2) on sister-chromatid exchange (SCE) frequencies and on human lymphocytes proliferation kinetics was studied. The results are compared with those of the P[N,N-bis(2-chloroethyl)amino]phenylacetate esters of 3 beta-hydroxy-17 alpha-aza-D-homo-5 alpha-androstan-17-one (compound 1). All compounds were found to be active in inducing markedly increased SCE rates and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumour activity of these compounds was observed.
Asunto(s)
Androstanos/toxicidad , Antineoplásicos/toxicidad , Azaesteroides/toxicidad , Linfocitos/efectos de los fármacos , Mutágenos/toxicidad , Compuestos de Mostaza Nitrogenada/toxicidad , División Celular/efectos de los fármacos , Células Cultivadas , Humanos , Intercambio de Cromátides Hermanas/efectos de los fármacosRESUMEN
The clastogenic activity of the antineoplastic alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam- p-bis (2-chloroethyl) aminophenoxy acetic acid (NSC 294859) and its congeners was studied in human lymphocyte cultures in vitro. Cells were exposed to several concentrations of the drugs for 24 h. It was found that NSC 294859 reduces the mitotic index and causes chromosome- as well as chromatid-type aberrations in a dose-dependent way. From its congeners, the alkylating agent (p-bis(2-chloroethyl)aminophenoxy acetic acid) induces the same phenomena but to a lesser extent, while the modified steroid (3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam) causes cytogenetic damages at the control level. These results favour the assumption that the antitumour activity of NSC 294859 is mainly based on its cytogenetic effects.
Asunto(s)
Antineoplásicos/farmacología , Aberraciones Cromosómicas , Compuestos de Mostaza Nitrogenada/farmacología , Alquilantes/farmacología , Androstanos/farmacología , Androstanos/toxicidad , Antineoplásicos/toxicidad , Azaesteroides/farmacología , Azaesteroides/toxicidad , División Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN , Relación Dosis-Respuesta a Droga , Humanos , Linfocitos/efectos de los fármacos , Índice Mitótico , Compuestos de Mostaza Nitrogenada/toxicidad , Análisis de RegresiónRESUMEN
The ortho, meta and para isomers of N,N-bis(2-chloroethyl)aminocinnamic acid were tested for their ability to mutate Salmonella typhimurium strains in the Salmonella/microsome mutagenicity test. The aim of the work was to establish a structure-activity relationship between these three isomers. The drugs were found to induce base-pair substitutions, causing dose-dependent increases in his+ revertants, in strains TA100 and TA1535. The study showed that the position of the substituent groups influenced the mutagenic activity of the compounds. The ortho isomer exhibited a poorer mutagenic effect than meta and this was found to be a weaker mutagen than para. The presence of metabolic activation enzymes in the test system induced a further increase in his+ revertants, in strains TA100 and TA1535, which is consistent with the findings for melphalan, a cancer chemotherapeutic agent with a chemical structure similar to that of the isomers tested.
Asunto(s)
Mostaza de Anilina/toxicidad , Pruebas de Mutagenicidad , Mutágenos/toxicidad , Mutación Puntual , Salmonella typhimurium/efectos de los fármacos , Mostaza de Anilina/química , Mostaza de Anilina/metabolismo , Distribución de Chi-Cuadrado , Cinamatos/química , Cinamatos/metabolismo , Cinamatos/toxicidad , Relación Dosis-Respuesta a Droga , Extractos Hepáticos , Microsomas Hepáticos/enzimología , Reproducibilidad de los Resultados , Salmonella typhimurium/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We studied the effects of caffeine alone or in combination with homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE, NSC 290205) on the frequency of SCEs and lymphocyte proliferation kinetics. Caffeine was found to act synergistically with ASE on the induction of SCEs when the two components were administered in combination. Caffeine was also found to act synergistically with ASE in inducing cell-division delays. Enhanced cytogenetic damage by ASE was observed when Ehrlich ascites tumour cells (EAT cells) were exposed in vivo to caffeine. ASE alone or in combination with caffeine caused a dose-dependent increase in SCE rates and cell-division delays. SCEs were demonstrated in EAT-bearing mice, by the i.p. injection of BrdUrd adsorbed onto activated charcoal, 1 h after the i.p. injection of ASE and/or caffeine.
Asunto(s)
Cafeína/toxicidad , Mutágenos , Compuestos de Mostaza Nitrogenada/toxicidad , Animales , Carcinoma de Ehrlich , División Celular/efectos de los fármacos , Células Cultivadas , Distribución de Chi-Cuadrado , Sinergismo Farmacológico , Ésteres , Humanos , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Intercambio de Cromátides Hermanas/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
The effect of modified steroids, containing alkylating agents, on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The homo-aza-steroidal ester of p-bis(2-chloroethyl)aminophenylacetic acid (ASE) was found to be the most effective in causing markedly increased SCE rates and cell division delays. The androsterone ester of p-bis(2-chloroethyl)aminophenylacetic acid (AE-CAPA) was found to be next in order of effectiveness with the lactone ester (LE-CAPA), chlorambucil ester 3 beta-hydroxy-13a-amino-13,17-seco-5a-androstan-17-oic-13,17-lactam (CBC-HAAL) and chlorambucil (CBC) following. p-Bis(2-chloroethyl)aminophenylacetic acid (CAPA) had only a small effect and 3 beta-hydroxy-13a-amino-13,17-seco-5a-androstan-17-oic-13,17-lactam (HAAL) had no effect at all. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumor activity of these drugs was observed.
Asunto(s)
Androstanos/toxicidad , Azaesteroides , Mutágenos/toxicidad , Compuestos de Mostaza Nitrogenada/toxicidad , Intercambio de Cromátides Hermanas/efectos de los fármacos , División Celular/efectos de los fármacos , Células Cultivadas , Humanos , Linfocitos/citología , Linfocitos/efectos de los fármacos , Pruebas de Mutagenicidad , Relación Estructura-ActividadRESUMEN
The effect of homo-azasteroidal esters of benzoic acid mustard isomers and the 4-methyl derivatives, which have steroidal lactams as a biological basis, on cytogenetic damage was studied. Twenty compounds were comparatively studied, on a molar basis, as regards their ability to induce sister-chromatid exchanges (SCEs) and cell division delays. A correlation between potency for SCE induction, effectiveness in cell division delay and previously established antitumor activity of these compounds was observed.
Asunto(s)
Azaesteroides/farmacología , División Celular/efectos de los fármacos , Mutágenos/farmacología , Compuestos de Mostaza Nitrogenada/farmacología , Intercambio de Cromátides Hermanas/efectos de los fármacos , Antineoplásicos/farmacología , Azaesteroides/química , Células Cultivadas , Humanos , Linfocitos/fisiología , Mutágenos/química , Compuestos de Mostaza Nitrogenada/químicaRESUMEN
A new homo-aza-steroidal ester, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenoxyaceta te gives a T/C greater than 125% in the treatment of P388 lymphoid leukemia. Modified and unmodified steroids without alkylating congener have been studied for activity in L1210 leukemia and EAT cells.
Asunto(s)
Antineoplásicos/uso terapéutico , Azaesteroides/uso terapéutico , Carcinoma de Ehrlich/tratamiento farmacológico , Leucemia P388/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Animales , Antineoplásicos/toxicidad , Azaesteroides/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intraperitoneales , Dosificación Letal Mediana , Leucemia L1210/tratamiento farmacológico , Leucemia P388/metabolismo , Ratones , Compuestos de Mostaza Nitrogenada/toxicidadRESUMEN
When cultures of human leukemia cells from 9 untreated patients with acute leukemia were treated with 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13, 17-lactam, an increased proliferating activity was exhibited. The leukemia cells were cultured for 48h and the amounts of lactam (4, 12 and 24 ng/ml) were added at zero time in the continuous presence of (3H)-thymidine. Our data suggested that in high concentrations lactam acts as a toxic agent while in the lower ones it seems to stimulate proliferation of the blast cell.
Asunto(s)
Androstanos , Azaesteroides/farmacología , Leucemia/fisiopatología , Esteroides Heterocíclicos/farmacología , Adulto , División Celular/efectos de los fármacos , Células Cultivadas , Humanos , Persona de Mediana Edad , Timidina/metabolismoRESUMEN
The effect of a homo-aza-steroidal ester (ASE) on the incorporation of radioactive precursor to DNA of Ehrlich ascites tumor (EAT) cells has been investigated. We found that treatment of cells with 80 micrograms/ml of ASE for 2 hours causes an inhibition of the incorporation of 3H-thymidine to DNA by 71%. This is partly because ASE affects the radioactive thymidine pool in the cell. The DNA from EAT cells after centrifugation in CsCl is shifted to higher densities when ASE is present throughout the experiment. This density shift was not observed when ASE was incubated only in the growth medium of the cells.