RESUMO
We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophosphamide (1000 muCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant. In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophosphamide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide.
Assuntos
Medula Óssea/patologia , Ciclofosfamida/efeitos adversos , Neoplasias/tratamento farmacológico , Ranitidina/uso terapêutico , Adulto , Contagem de Células Sanguíneas/efeitos dos fármacos , Ciclofosfamida/farmacocinética , Ciclofosfamida/uso terapêutico , Método Duplo-Cego , Humanos , Taxa de Depuração Metabólica , Ranitidina/farmacocinéticaRESUMO
A one-step synthesis of 4-hydroperoxyifosfamide and 4-hydroperoxytrofosfamide is described. The method involves direct ozonation of ifosfamide and trofosfamide and offers improved yields in comparison with Fenton oxidation and greater convenience in comparison with ozonation of the appropriate 3-butenyl phosphorodiamidate. Evaluation of the 4-hydroperoxy derivatives of cyclophosphamide, ifosfamide, and trofosfamide against leukemia L1210 in vivo suggests a superior effect for the ifosfamide derivatie.
Assuntos
Ciclofosfamida/análogos & derivados , Ifosfamida/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fenômenos Químicos , Química , Ciclofosfamida/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Ifosfamida/uso terapêutico , Leucemia L1210/tratamento farmacológico , OzônioRESUMO
Incubation at approximately physiological conditions of amino acids, peptides, and proteins with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or cyclohexyl isocyanate resulted in carbamoylation of the alpha-amino groups of amino acids, the terminal amino groups of peptides and proteins and the epsilon-amino groups of lysine moieties. Carbamoylation of the alpha-amino groups and the terminal amino groups occurred as readily as, or more readily than, the carbamoylation of the epsilon-amino groups. Carbamoylation of the amino groups of amino acids or peptides by 1,3-bis(2-chloroethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea altered the electrophoretic mobility of those compounds. Cyclization of (2-cloroethylcarbamoyl)-amino groups to form (2-oxazolin-2-yl)amino groups occurred at room temperature, and the resulting oxazolinyl compounds migrated electrophoretically similarly to the parent compounds. Since such cyclization did not occur with cyclohexylcarbamoylamino groups, treatment of amino acids, peptides, or proteins with 1,3-bis(2-chloroethyl)-1-nitrosourea might result in less permanent alteration of the respective charges on the resulting products than would treatment with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or other nitrosoureas lacking a 2-chloroethyl group on N-3. The relevance of these differences in charge to differences in physiological effects is not presently known. Although the present study does not establish a definite relationship between carbamoylation of any specific protein and the physiological effects of nitrosourea, it does reinforce and expand the existing evidence that carbamoylation of proteins is a proteins is a process that must be considered in efforts to explain the physiological effects of these agents, and it points to terminal amino groups of proteins as possible primary sites of carbamoylation.
Assuntos
Aminoácidos , Carbamatos , Compostos de Nitrosoureia/farmacologia , Peptídeos , Proteínas , Sítios de Ligação , Lisina , Relação Estrutura-AtividadeRESUMO
N, N-Bis (2-chloroethyl)-N-nitrosourea (BCNU) is a substrate for a microsomal enzyme of mouse liver. The reaction requires NADPH, and the product is 1, 3-bis (2-chloroethyl) urea. This activity is also found in mouse lungs but not in several other tissues. With reaction conditions under which BCNU is not chemically degraded, the Km for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a Ki of 0.6 mM. N-Methyl-N-nitrosourea is denitrosated in a similar reaction. N- (2-Chloroetyhy)- N-cyclohexyl-N-nitrosourea and N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea are also substrates for microsomal enzymes, but the products of these reactions are ring-hydroxylated derivatives. The Km value for N-(2-CHLOROETHYL)-N-cyclohexyl-N-nitrosourea is 3.0 mM and that for N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea is 1.0 mM. The hydroxylase activity is also present in lungs, but not in the other mouse tissues. The rates of microsomal metabolism of BCNU, N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl-N-(trans-4-methylcyclohexyl)-N-nitrosourea are fast enough to allow metabolism of large portions of administered doses before chemical decomposition of the drugs occurs.
Assuntos
Microssomos Hepáticos/enzimologia , Compostos de Nitrosoureia/metabolismo , Animais , Ligação Competitiva , Radioisótopos de Carbono , Carmustina/metabolismo , Fracionamento Celular , Fenômenos Químicos , Química , Cicloexanos , Ciclofosfamida/metabolismo , Feminino , Técnicas In Vitro , Pulmão/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos DBA , Oxigenases de Função Mista/metabolismo , NADP , Nicotina/metabolismoRESUMO
Biochemical investigations relating to the mechanism of action and mechanism of activation have been made for the carcinogen, 4-chloro-2-methylaniline. Radioactivity from 4-chloro-2-[methyl-14C]methylaniline became extensively bound to protein, DNA, and RNA of rat liver, but macromolecules of some of the other tissues examined contained little radioactivity. Enzymatic activity dependent upon reduced nicotinamide adenine dinucleotide and leading to irreversible binding to radioactivity from labeled 4-chloro-2-methylaniline to macromolecules in the reaction system was present in microsomes from rat liver. The activity was inducible by phenobarbital. Two soluble products of microsomal enzymes were identified by mass spectral analysis and chemical synthesis as 5-chloro-2-hydroxylaminotoluene and 4,4'-dichloro-2,2'-dimethylazobenzene. The hydroxylamino compound appears to be a more activated form of 4-chloro-2-methylaniline.
Assuntos
Compostos de Anilina/metabolismo , Carcinógenos/metabolismo , DNA/metabolismo , Proteínas/metabolismo , RNA/metabolismo , Animais , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Oxirredução , Fenobarbital/farmacologia , RatosRESUMO
4-Methylcyclophosphamide was synthesized and separated into cis and trans isomers by column chromatography. Isolation of these isomers permitted individual evaluation against murine leukemia L1210 in vivo and assessment of possible differences in antileukemic activity. Results indicate no appreciable difference in activity of the isomers, suggesting essentially equal facility for activation by mouse liver microsomes in vivo.
Assuntos
Ciclofosfamida/análogos & derivados , Leucemia L1210/tratamento farmacológico , Animais , Cromatografia em Gel , Cromatografia em Camada Fina , Ciclofosfamida/isolamento & purificação , Ciclofosfamida/uso terapêutico , Camundongos , Microssomos Hepáticos/efeitos dos fármacosRESUMO
We examined the metabolism and disposition of aniline, which induces spleen hemangiosarcomas in rats but no tumors in mice, in normal and predosed Fischer 344 rats, and C57BL/6 X C3H F1 mice administered low (50 and 100 mg/kg, respectively) or high (250 and 500 mg/kg, respectively) doses. Of 11 tissues examined, the highest levels of binding of [14C]aniline to DNA were in the kidney, large intestine, and spleen of high-dose rats that had received prior dosing; these tissues had covalent binding indices of 14.2, 4.3, and 3.7 mumol/mol nucleotides/dose, respectively. Protein and RNA were the major macromolecular targets for binding of radioactivity from [14C]aniline. Relative to controls, most tissues from predosed mice (low dose and high dose) showed less binding to protein and RNA; but for most tissues from predosed rats administered 50-mg/kg doses of [14C]aniline, there was more extensive binding. Also relative to controls, binding of radioactivity in the spleen of predosed rats given [14C]aniline (50 mg/kg) was 148% greater for protein and 302% greater for RNA. For rats administered 250 mg of [14C]aniline per kg, however, there were no outstanding differences in binding to RNA and protein between normal and predosed animals. The profiles of urinary metabolites produced by rats and mice were not appreciably different in animals predosed with aniline. For rats, however, the profiles were different for the low and high doses, suggesting that the main metabolic pathway was saturated at the higher dose. p-Acetamidophenyl sulfate represented over 70% of the total radioactivity recovered from the urine of rats dosed with 50 mg of aniline per kg but only 30% in the urine of those dosed with 250 mg/kg. The urine of the high-dose rats contained greater percentages of p-aminophenyl sulfate, p-acetamidophenyl glucuronide, and unconjugated metabolites. In mouse urine, p-acetamidophenyl glucuronide, representing 29 to 32% of the total radioactivity, was the major metabolite. Nevertheless, mice produced more ortho derivatives than did rats, for in acid-treated urine, the ratio of p- to o-aminophenol was 8.1 for rats and 1.6 for mice. Predosing of rats and mice did not change the kinetic values for liver aniline p-hydroxylase or N-hydroxylase but increased the amount of mouse liver cytochrome P-450 from 0.231 to 0.491 nmol/mg protein. For p-hydroxylase of rat liver, the apparent Km value was higher, and the apparent Vmax value lower than in mouse liver. Kinetic values for rat and mouse N-hydroxylase were similar.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Compostos de Anilina/metabolismo , Compostos de Anilina/farmacologia , Animais , Radioisótopos de Carbono , Sistema Enzimático do Citocromo P-450/metabolismo , DNA/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Oxigenases de Função Mista/metabolismo , Proteínas/metabolismo , RNA/metabolismo , Ratos , Ratos Endogâmicos F344 , Especificidade da Espécie , Distribuição TecidualRESUMO
Since cyclophosphamide is used by both oral and i.v. routes in the treatment of hematological and solid malignancies, we designed a randomized, crossover clinical trial to evaluate the pharmacokinetics of this anticancer agent after either administration route. Plasma levels of cyclophosphamide and its two cytotoxic metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard, were determined in seven cancer patients randomly assigned to treatment initially with either orally or i.v. administered cyclophosphamide with a 30-day interim between alternate therapy courses. Oral treatment was used initially in five patients and i.v. treatment in two patients, and the pharmacokinetic parameter, area under the plasma disappearance curve, was determined for each metabolite in each patient for both routes of drug administration. Statistical comparison of area under the plasma disappearance curve values for this set of patients indicated no significant differences for either metabolite for oral versus i.v. drug treatment, suggesting equal efficacy for these two routes of cyclophosphamide administration.
Assuntos
Ciclofosfamida/sangue , Administração Oral , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Ciclofosfamida/análogos & derivados , Humanos , Injeções Intravenosas , Cinética , Mostardas de Fosforamida/sangue , Distribuição AleatóriaRESUMO
One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
Assuntos
Acetilcisteína/farmacologia , Ciclofosfamida/efeitos adversos , Mercaptoetanol/análogos & derivados , Mesna/farmacologia , Oxigenases de Função Mista/metabolismo , Oxirredutases/metabolismo , Bexiga Urinária/efeitos dos fármacos , Aminopirina N-Desmetilase/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Ciclofosfamida/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Leucopenia/induzido quimicamente , Fígado/enzimologia , Masculino , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Penclomedine [3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine], an antitumor agent, is currently in Phase I clinical trials and is believed to be a prodrug. In these studies, cerebellar effects have been dose limiting. Previous studies identified 4-demethylpenclomedine (4-DM-PEN) as the major plasma metabolite in rodents and humans. 4-DM-PEN was demonstrated to be an antitumor-active metabolite of penclomedine in vivo when evaluated against the penclomedine-sensitive MX-1 human breast tumor xenograft implanted either s.c. or intracerebrally and is believed to be on the metabolic activation pathway of penclomedine. Because earlier studies revealed an absence of neurotoxic cerebellar effects for 4-DM-PEN in contrast to penclomedine in a rat model, this metabolite may be a candidate for an alternative to penclomedine in the clinic for treatment of breast cancer or brain tumors, if the cerebellar effects of penclomedine preclude its further clinical development. Because neither penclomedine nor 4-DM-PEN were very active in vitro, the metabolism of penclomedine was also investigated using rat liver microsomes in an attempt to identify the ultimate active form of the drug. Metabolites and putative metabolites were prepared by chemical synthesis for antitumor evaluation in vitro and in vivo. A reductive metabolite, alpha,alpha-didechloro-PEN, was observed to be much more cytotoxic than penclomedine or 4-DM-PEN in vitro, but evaluation of this and the other metabolites and putative metabolites in vivo against the MX-1 tumor failed to identify any active metabolite among the structures evaluated other than 4-DM-PEN. The limited activity of 4-DM-PEN in vitro indicates that it, like penclomedine, is also a prodrug, demonstrating a need for additional studies on the metabolic activation of penclomedine to identify the ultimate active form of the drug.
Assuntos
Antineoplásicos/química , Picolinas/química , Animais , Biotransformação , Neoplasias da Mama/tratamento farmacológico , Humanos , Leucemia P388/tratamento farmacológico , Masculino , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Picolinas/efeitos adversos , Picolinas/metabolismo , Picolinas/uso terapêutico , Picolinas/toxicidade , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
Studies on the in vivo and in vitro disposition of 4,4'-[14C]-methylenebis(N,N-dimethyl)benzamine (reduced Michler's ketone, RMK) were performed. Osborne-Mendel rats retained, after 24 hr, 78% of a p.o. dose of [14C]RMK. At 24 hr after an i.p. dose, fat, liver, and intestine represented major sites for deposition of radioactivity. The major urinary metabolite of RMK, representing 36% of the total radioactivity recovered in the urine, was N,N'-diacetyl-4,4'-(hydroxymethylene)dianiline. In vitro microsomal metabolism of RMK involved demethylation. Products included N,N-dimethyl-4,4'-methylenedianiline, N,N'-dimethyl-4,4'-methylenedianiline, N-methyl-4,4'-methylenedianiline, and 4,4'-methylenedianiline, representing 44.7, 5.3, 11.8, and 6.9%, respectively, of the total radioactivity recovered from the reaction mixture. Although none of the microsomal metabolites was a direct-acting mutagen in the standard Salmonella typhimurium assay, all could be activated to mutagens when incubated with 9000 X g liver supernatants and reduced nicotinamide adenine dinucleotide phosphate. The activation of 4,4'-methylenedianiline to a mutagen suggests that the methyl groups of RMK are not required for the conversion of RMK to a reactive electrophile.
Assuntos
Tecido Adiposo/metabolismo , Compostos de Anilina/metabolismo , Carcinógenos/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Animais , Biotransformação , Microssomos Hepáticos/metabolismo , Mutagênicos , Ratos , Distribuição TecidualRESUMO
The hepatic cytochrome P-450-mediated metabolism and metabolic activation of [chloroethyl-3H]cyclophosphamide [( chloroethyl-3H]CP) and [4-14C]cyclophosphamide [( 4-14C]CP) were investigated in vitro in the reconstituted system containing cytochrome P-450 isolated from phenobarbital-treated rats. In addition, hepatic microsomal binding and the hepatic microsome-mediated metabolism of [14C]acrolein, a metabolite of [4-14C]CP, were also investigated. The metabolism of [chloroethyl-3H]CP and [4-14C]CP to polar metabolites was found to depend on the presence of NADPH and showed concentration dependence with respect to cytochrome P-450 and NADPH:cytochrome P-450 reductase. Km and Vmax values were essentially similar (Km, 0.44 and 0.42 mM; Vmax, 4.8 and 7.0 nmol of polar metabolites formed/min/nmol of cytochrome P-450 for [4-14C]CP and [chloroethyl-3H]CP, respectively). The patterns of inhibition by microsomal mixed-function oxidase inhibitors, anti-cytochrome P-450 antibody, and heat denaturation of the cytochrome P-450 were essentially similar, with subtle differences between [4-14C]CP and [chloroethyl-3H]CP metabolism. The order of inhibition by various mixed-function oxidase inhibitors was SKF greater than alpha- and beta-naphthoflavones greater than metyrapone. The in vitro metabolic activation of CP in the reconstituted system demonstrated predominant binding of [chloroethyl-3H]CP to nucleic acids and almost exclusive binding of [4-14C]CP to proteins. Gel electrophoresis-fluorography of the proteins in the reconstituted system treated with [4-14C]CP demonstrated localization of the 14C label in the cytochrome P-450 region. To examine this association further, hepatic microsomes were modified with [14C]acrolein in the presence and the absence of NADPH. The results confirmed covalent association between [14C]acrolein and cytochrome P-450 in the microsomes and also demonstrated further metabolism of [14C]acrolein, apparently to an epoxide, which is capable of binding covalently to proteins. The results of these investigations not only confirm the significance of primary metabolism but also emphasize the potential role of the secondary metabolism of cyclophosphamide in some of its toxic manifestations.
Assuntos
Acroleína/metabolismo , Aldeídos/metabolismo , Ciclofosfamida/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Microssomos Hepáticos/metabolismo , Animais , Radioisótopos de Carbono , Escherichia coli , Cinética , Masculino , Oxigenases de Função Mista/metabolismo , Ligação Proteica , RNA de Transferência/metabolismo , Ratos , Ratos Endogâmicos , TrítioRESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Doenças do Sistema Nervoso Central/induzido quimicamente , Neoplasias/tratamento farmacológico , Picolinas/efeitos adversos , Adulto , Idoso , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Picolinas/farmacocinética , Picolinas/uso terapêutico , Contagem de Plaquetas/efeitos dos fármacosRESUMO
Penclomedine, a lipophilic alpha-picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of penclomedine and penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c. tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the plasma radioactivity. Penclomic acid was also the most common urinary metabolite of penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in tumors and all other tissues, penclomedine was the main compound detected. The finding of penclomedine in normal brain tissue indicates not only that this drug may be useful in tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias Experimentais/metabolismo , Picolinas/farmacocinética , Animais , Autorradiografia , Encéfalo/metabolismo , Radioisótopos de Carbono , Rim/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Because certain (2-chloroethyl)triazenes and (2-haloethyl)nitrosoureas have high antineoplastic activity, 2-chloroethyl and 2-fluoroethyl sulfonates were prepared to try to develop additional types of 2-haloethylating agents. In this initial study, it was demonstrated that antineoplastic activity much superior to that of the prototype, 2-chloroethyl methanesulfonate, could be found among 2-chloroethyl sulfonates. Among a variety of 2-chloroethyl alkane- and arenesulfonates, several substituted methanesulfonates displayed significant activity against P388 leukemia in mice; the chloromethanesulfonate showed high activity (T/C = 218%). None of the arenesulfonates were active in this test.
Assuntos
Compostos de Mostarda/síntese química , Ácidos Sulfônicos/síntese química , Animais , Antineoplásicos/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Leucemia L1210/patologia , Leucemia P388/patologia , Camundongos , Compostos de Mostarda/farmacologia , Ácidos Sulfônicos/farmacologiaRESUMO
Spirohydantoin mustard (SHM), a central nervous system directed nitrogen mustard with anticancer activity, was metabolized in the presence of mouse liver postmitochondrial supernatant (9000g fraction) to a nonpolar alkylating metabolite. The metabolite was isolated by thin-layer chromatography of chloroform or ethyl acetate extracts of incubation mixtures, and its structure was established by mass spectral analysis, synthesis, and cochromatography. The metabolite, spirohydantoin aziridine, was mutagenic for Salmonella typhimurium TA1535 in the Ames assay but inactive as an antitumor agent against P388 leukemia in vivo.
Assuntos
Antineoplásicos/síntese química , Aziridinas/síntese química , Azirinas/síntese química , Mutagênicos/síntese química , Animais , Aziridinas/farmacologia , Aziridinas/uso terapêutico , Biotransformação , Avaliação Pré-Clínica de Medicamentos , Leucemia P388/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Testes de Mutagenicidade , Mutação , Salmonella typhimurium/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Iminocyclophosphamide (4) has been identified by 1H NMR as a product from base treatment of 4-alkylthio-substituted cyclophosphamide derivatives, viz., cis-4-(propylthio)cyclophosphamide (cis-7). A maximum concentration of approximately 12% of total product was observed by treating cis-7 with ethyl propiolate and NaH or deuteriated dimsyl anion in anhydrous Me2SO-d6. Treatment of cis-7 with base alone established a rapid cis-/trans-7 equilibrium via the imine intermediate 4. Base-catalyzed expulsion of 1-propanethiol (8) from cis-7 and thiol trapping afforded formation of 4, which subsequently underwent elimination to the relatively more stable conjugated (vinylimino)-phosphamide (9). Iminocyclophosphamide (4) was also identified by fast atom bombardment mass spectrometry as a product generated upon analysis of cyclophosphamide derivatives substituted in the 4-position of the oxazaphosphorine ring with various leaving groups.
Assuntos
Ciclofosfamida/análogos & derivados , Ciclofosfamida/metabolismo , Ciclofosfamida/análise , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
Seven new (2-chloroethyl)nitrosocarbamates have been synthesized as potential anticancer alkylating agents. These compounds were designed with carrier moieties that would either act as prodrugs or confer water solubility. All compounds were screened in an in vitro panel of five human tumor cell lines: CAKI-1 (renal), DLD-1 (colon), NCI-H23 (lung), SK-MEL-28 (melanoma), and SNB-7 (CNS). Several agents showed good activity with IC(50) values in the range of 1-10 microg/mL against at least two of the cell lines. One compound, carbamic acid, (2-chloroethyl)nitroso-4-acetoxybenzyl ester (3), was selected for further study in vivo against intraperitoneally implanted P388 murine leukemia. In addition to the aforementioned compound, both carbamic acid, (2-chloroethyl)nitroso-4-nitrobenzyl ester (9) and carbamic acid, (2-chloroethyl)nitroso-2,3,4, 6-tetra-O-acetyl-1-alpha,beta-D-glucopyranose ester (24) were evaluated against subcutaneously implanted M5076 murine sarcoma in mice. None of these compounds were active in vivo.
Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Compostos Nitrosos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Transplante de Neoplasias , Compostos Nitrosos/química , Compostos Nitrosos/farmacologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Evidence at the molecular level is presented in support of alkylation of O6-guanine moieties of DNA as the mechanism of cytotoxicity of Clomesone to HT-29 cells and consists in the isolation and identification of a product resulting from alkylation of calf thymus DNA with Clomesone, followed by depurination to yield 7-(2-hydroxyethyl)guanine, whose formation is reasonably explained by O6-guanine chloroethylation followed by intramolecular alkylation at N7 of guanine and subsequent hydrolysis to the hydroxyethylguanine.
Assuntos
Antineoplásicos , DNA/metabolismo , Guanina/análogos & derivados , Mesilatos/farmacologia , Timo/metabolismo , Alquilação , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Guanina/análise , Guanina/isolamento & purificação , Hidrólise , Metilação , Timo/efeitos dos fármacosRESUMO
The metabolism of spirohydantoin mustard (SHM), a central nervous system-directed nitrogen mustard with reported anticancer activity, was studied using both the Salmonella/mammalian microsome mutagenicity assay and radiolabeled drug. SHM had little or no mutagenic activity by itself but was metabolized to a mutagen(s) in the presence of mouse postmitochondrial liver fraction (9000 g supernatant, S9). Metabolism was NADPH-dependent and was enhanced with phenobarbital-induced S9. Both SHM and mutagen(s) were extractable in chloroform. Studies using [14C]SHM, uniformly labeled on the bis(2-chloroethyl)amino group, and thin-layer chromatography (TLC) of chloroform extracts of liver S9 incubation mixtures indicated the formation of a single major metabolite fraction that contained a direct-acting mutagen. Chloroform extracts of both blood and brain from BDF1 mice injected i.p. with SHM (60 mg/kg) were found to be mutagenic in the absence of S9. Also, TLC of chloroform extracts of brain taken 15 min after i.p. injection of [14C]SHM suggested the presence of SHM and the mutagenic metabolite. These results suggest that the mutagenic metabolite may have a significant role in the mechanism of action of SHM.