RESUMO
PURPOSE: Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks. PATIENTS AND METHODS: Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria. RESULTS: The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis. CONCLUSION: Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Europa (Continente) , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Infusões Intravenosas , Avaliação de Estado de Karnofsky , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Indução de Remissão , Taxa de SobrevidaRESUMO
PURPOSE: To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS: Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS: Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION: An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Dinamarca , Relação Dose-Resposta a Droga , Esquema de Medicação , Epirubicina/efeitos adversos , Epirubicina/farmacocinética , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Pós-Menopausa , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do TratamentoRESUMO
Fourteen cancer patients treated with cisplatin received repeated infusions of tropisetron on-demand in conjunction with emesis. In subsequent chemotherapy courses, prophylactic tropisetron was given in a dose identical to the cumulated dose in study course 1. Tropisetron in study course 1 abolished emesis after 7.5 min (5 mg). Duration of effect was more than 7 h in 50% of the patients. No relationship between dose and duration of effect was seen. After study course 2, eight of 10 patients preferred prophylactic tropisetron. Two patients with hypertension had a severe increase in blood pressure probably related to tropisetron. It is concluded that tropisetron has an instant and lasting effect on nausea and vomiting when given on-demand. The majority of patients, however, prefer prophylactic treatment. Hypertension may be a side effect from tropisetron and caution should be displayed in hypertensive patients.
Assuntos
Antieméticos/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Indóis/uso terapêutico , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Antagonistas da Serotonina/uso terapêutico , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Adulto , Idoso , Antieméticos/administração & dosagem , Antieméticos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Náusea/prevenção & controle , Neoplasias Ovarianas/complicações , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacocinética , Tropizetrona , Vômito/prevenção & controleRESUMO
The effect of radiotherapy alone or given simultaneously with 5-FU in the treatment of locally recurrent or inoperable colorectal carcinoma was investigated in a randomized feasibility trial. Twenty-nine patients were randomized to radiotherapy alone (50 Gy/5 weeks + 10-20 Gy boost), and 30 patients to the same radiotherapy with weekly 5-FU (600 mg/m2) given before treatment every Monday during the first 5 weeks. The two groups were comparable with regard to age, sex, previous treatment, symptoms, tumour size and performance status. Treatment compliance to radiotherapy was the same in both groups with 87% receiving at least 50 Gy. Drug treatment was completed in 18/30 patients. Overall the treatment resulted in a significant palliative effect in 73% of evaluable patients with a median duration of 26 months, and objective response in 32% (8 CR, 11 PR), with a median duration of 18 months. The 3-year actuarial survival rate was 9% (median 12 months). Only patients who achieved CR became long-time survivors (63% 3-year actuarial survival). Similarly, performance status had a strong association with survival. Multivariate analysis showed complete response and high performance status to be the only parameters having prognostic influence on survival. Addition of 5-FU did neither influence the objective or symptomatic response, nor the development of distant metastases. However, addition of the drug resulted in an apparent increase in the frequency of severe acute radiation complications (33% vs. 13% after irradiation alone).
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Fluoruracila/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Detailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m2 given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. A similar correlation was observed when the metabolite epirubicinol was also considered. The decrease in leucocyte count as expressed by the logarithmic ratio between nadir WBC and initial WBC was linearly correlated with the AUC of either epirubicin alone (r = -0.55, P less than 0.001) or epirubicin and epirubicinol together (r = -0.63, P less than 0.001). As a relationship between the concentration of epirubicin in a single plasma sample taken at 6 h following i.v. administration and the AUC of the drug has been established, a log-linear relationship between the expected decrease in leucocytes and the concentration at 6 h after administration could be calculated. The proposed model is expressed as the equation: log WBCnadir = log WBCinitial -0.0073 x c6 (ng/ml)-0.14.
Assuntos
Medula Óssea/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Epirubicina/administração & dosagem , Neoplasias da Mama/sangue , Relação Dose-Resposta a Droga , Doxorrubicina/análogos & derivados , Doxorrubicina/sangue , Epirubicina/efeitos adversos , Epirubicina/sangue , Feminino , Humanos , Infusões Intravenosas , Contagem de Leucócitos/efeitos dos fármacos , Prognóstico , Análise de Regressão , Fatores de TempoRESUMO
The possibility that verapamil might increase the sensibility of colorectal carcinomas to doxorubicin was studied in 24 patients without previous cytotoxic chemotherapy. The treatment started with oral verapamil, which was escalated up to the individual maximum tolerable dose (defined by prolongation of P-Q in ECG, fall in blood pressure, or dizziness). The median maximum tolerable dose was 600 mg (range 320-1,440 mg). During continued verapamil administration the patients then got weekly infusions of doxorubicin, 25 mg/m2. The median number of doxorubicin courses was 8 (range 2-22). Among 21 patients evaluable for response and toxicity two partial remissions occurred but no complete remission. The study did not indicate enhanced cardiac, hematological or non-hematological toxicity from the combined treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Verapamil/administração & dosagem , Verapamil/efeitos adversosRESUMO
Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m2. In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (mean t1/2 gamma, 21.6 +/- 7.9 h; range, 10.6-69 h; n = 110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (mean t1/2 gamma, 18.1 +/- 4.8 h; range, 8.2-38.4 h; n = 105). Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (mean t1/2 gamma, 13 +/- 4.6 h; range, 2.7-29 h; n = 104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC = 9.44 x c2 + 62.5 x c24 + 157.7 (r = 0.953).
Assuntos
Neoplasias da Mama/tratamento farmacológico , Epirubicina/farmacocinética , Neoplasias da Mama/sangue , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Epirubicina/administração & dosagem , Epirubicina/sangue , Feminino , Meia-Vida , HumanosRESUMO
A phase II study of cisplatin and tegafur in recurrent epidermoid head and neck cancer is presented. All patients were treated with cisplatin 100 mg/m2 every 4 weeks. Twenty-nine received tegafur 750 mg/m2 days 2-28 orally and 18 patients, who were unable to take tegafur orally, were treated with tegafur 1,500 mg/m2 intravenously days 2-5. The response rate in the oral group was 28.5% and the median survival 29 weeks. The response rate in the intravenous group was 6% and the median survival was 17 weeks. We conclude that cisplatin and oral tegafur is active against head and neck cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Tegafur/uso terapêutico , Administração Oral , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Tegafur/administração & dosagemRESUMO
Sixty postmenopausal women with advanced breast cancer entered a phase II study, evaluating idarubicin (IDA) in a weekly schedule. Starting dose was 22.5 mg/m2, and median age was 65 years. Five patients were considered ineligible and the response rate among 55 eligible patients was 33%. Median time to treatment failure was 19 weeks and median duration of tumor regression for 18 responding patients was 40 weeks. Hematologic toxicity was moderate and non-hematologic toxicity was mild. The study shows that IDA, administered orally in a weekly schedule, has pharmacodynamic properties comparable to IDA in a 3-weekly schedule and to doxorubicin in the treatment of advanced breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Idarubicina/administração & dosagem , Administração Oral , Adulto , Idoso , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Humanos , Idarubicina/uso terapêutico , Menopausa , Pessoa de Meia-IdadeRESUMO
Epirubicin (Farmorubicin) is a drug of significant interest in the treatment of a variety of solid tumours and a comprehensive review of reported investigations is given. From experimental and clinical studies it appears that in general doxorubicin and epirubicin exhibit no qualitative, but only some quantitative, differences. Thus, the pharmacokinetic and pharmacodynamic characteristics of the two drugs are essentially similar, as are the tumour spectrum and the level of their clinical efficacies. To achieve haematological equitoxicity of the two drugs the dose of epirubicin should be approximately 20% higher than that of doxorubicin, giving rise to a higher cumulative dose of epirubicin. On the other hand, epirubicin is significantly less cardiotoxic than doxorubicin. Thus, the recommended cumulative dose of doxorubicin is 500 mg/m2 and the corresponding figure for epirubicin is 1,000 mg/m2. For either drug a number of questions are still left open, the most important of which include the questions about optimal treatment schedules and the existence of a clinical relevant dose/efficacy relationship.
Assuntos
Epirubicina/uso terapêutico , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistência a Medicamentos , Epirubicina/efeitos adversos , Epirubicina/farmacocinética , HumanosRESUMO
The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer. Plasma concentrations were monitored for 72 hours after the first, fourth, and twelfth doses and trough concentrations after 1, 2, 3, 4, 5, 7, 11, and 12 weeks of treatment. The half-lives of idarubicin and idarubicinol were 19 and 60 hours, respectively. No time-dependent changes or cumulation were observed. The metabolic ratio showed little variation. The plasma AUCs of idarubicin and idarubicinol varied between patients but were fairly constant in individual patients. The sum of the plasma AUCs was lower in patients with rapid progression than in patients who responded to treatment. A correlation between this parameter and the relative decrease in the leukocyte counts was demonstrated (p less than 0.05). No correlation was found between the pharmacokinetic parameters and the time to final progression.
Assuntos
Neoplasias da Mama/metabolismo , Idarubicina/farmacocinética , Administração Oral , Idoso , Disponibilidade Biológica , Neoplasias da Mama/tratamento farmacológico , Daunorrubicina/análogos & derivados , Daunorrubicina/farmacocinética , Meia-Vida , Humanos , Idarubicina/efeitos adversos , Idarubicina/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
Idarubicin (IDA), a more lipophilic derivative of daunorubicin, has shown activity after oral administration. In November 1983 we initiated a phase II study administering IDA, 45 mg/m2, in a 3 weekly schedule as first line chemotherapy to postmenopausal women with advanced breast cancer. Among 50 eligible patients a response rate of 36% (95% confidence interval (CI): 23-51) was obtained. Median time to treatment failure was 22 weeks (95% CI: 15-32). In November 1986, a sequential phase II study with IDA given in a weekly schedule was initiated. Patient characteristics was comparable to the first study. Among 53 evaluable patients, the response rate was 34% (95% CI: 22-48), and median time to treatment failure was 19 weeks (95% CI: 13-33). Therapeutic efficacy in the two studies was comparable and similar to published data on doxorubicin. Hematologic toxicity was equal while non-hematologic toxicity was considerably lower in the weekly schedule. A phase III comparison of IDA to doxorubicin or epi-doxorubicin is warranted, in order to clarify the role of IDA in the treatment of advanced breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Idarubicina/administração & dosagem , Administração Oral , Adulto , Idoso , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Humanos , Idarubicina/efeitos adversos , Leucopenia/induzido quimicamente , Pessoa de Meia-IdadeRESUMO
The current attempts to cure cancer of the esophagus have been reviewed. Evaluating the results of treatment is an exercise in assessing varying degrees of failure. Furthermore, selection biases make meaningful comparison of the results difficult. The results of surgical, radiotherapeutical, and chemotherapeutical treatment as single modality treatment seem quite similar, although a reduction of the postoperative mortality has been reported from various centres. The results of combined modality treatment indicate that it is possible to render some patients tumorfree at the time surgery by preoperative treatment, but this therapeutical gain has not so far increased the 5-year survival of the entire treated group. The results of combined modality treatment without surgery is favoured by absence of postoperative mortality.
Assuntos
Neoplasias Esofágicas/terapia , Antineoplásicos/uso terapêutico , Terapia Combinada , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/cirurgia , HumanosRESUMO
The common side effects of doxorubicin (DOX) treatment, i.e. vomiting and diarrhoea, would be expected to alter the pharmacokinetics of DOX in man, the efficacy of treatment, and further aggravate the side effects through acid/base disturbances. The pharmacokinetics were therefore investigated in 4 anthracycline naive females with advanced mammary carcinoma in 2 series of DOX monotherapy 70 mg/m2 administered with an interval of 4 weeks between the treatments. Sequential loading either with acid or base was instituted 2 days before and continued for 2 days after DOX infusion. Median urine pH was 5.0 or 8.0, and median arterial blood pH 7.30 or 7.43 respectively. Plasma and urine samples were analyzed by high performance liquid chromatography (HPLC). No difference was seen between the acid and alkaline condition for DOX or doxorubicinol with regard to clearance from blood plasma, area under the curve, renal clearance, renal drug clearance/renal creatinine clearance. Thus moderate acid/base metabolic disturbances did not alter the pharmacokinetics of DOX up to 48 h after DOX infusion.
Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Doxorrubicina/farmacocinética , Adulto , Bicarbonatos/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Diarreia/induzido quimicamente , Diarreia/metabolismo , Doxorrubicina/efeitos adversos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Rim/metabolismo , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Urina , Vômito/induzido quimicamente , Vômito/metabolismoRESUMO
In a phase I trial 4-demethoxydaunorubicin (4-dm DNR) was administered as oral capsules once a week to 51 adults with advanced mainly gastrointestinal solid tumors. No fatal toxicity was observed at doses up to 25.0 mg/m2. Dose-limiting granulocytopenia and non-hematologic toxicity developed at dosages greater than or equal to 22.5 mg/m2. No response to the therapy was observed. The plasma concentrations of 4-dm DNR were measured in 4 of the patients.
Assuntos
Idarubicina/efeitos adversos , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacocinética , Masculino , Pessoa de Meia-IdadeRESUMO
A phase II study of 4-demethoxydaunorubicin (idarubicin) administered orally (45 mg/m2) every 3 weeks was conducted in patients with anthracycline-naive advanced breast cancer. Fifty patients were eligible to enter the trial; the median time to disease progression for all 50 patients entered was 22 weeks. Four patients achieved complete response and 14 achieved partial response. Response rate was 36% (complete response + partial response) for all patients entered. The median duration of tumor regression was 39 weeks. The treatment toxic effects observed were both hematologic and nonhematologic and of moderate degrees. Hair loss was observed in 86% of the patients, nausea and vomiting in 96%, and diarrhea in 36%. Cardiac function was monitored with isotope angiocardiography and no patients developed clinical congestive heart failure, up to a median cumulative dose of 260 mg/m2. The left ventricular ejection fraction decreased with a median value of 4% in seven patients treated with greater than 360 mg/m2. This study indicates that idarubicin administered orally has pharmacodynamic effects comparable to those of doxorubicin administered iv on an every-3-week schedule.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Daunorrubicina/análogos & derivados , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Avaliação de Medicamentos , Feminino , Humanos , Idarubicina , Pessoa de Meia-IdadeRESUMO
The pharmacokinetics of doxorubicin in rabbits preloaded either with ammonium chloride or sodium hydrogencarbonate have been investigated following single IV administration of 5 mg/kg. Plasma samples and urine collections were obtained over 3 h following administration, and were assayed in duplicate for doxorubicin and its main metabolite doxorubicinol by reversed-phase high-pressure liquid chromatography. The plasma concentration of doxorubicin was fitted to an open two-compartment model. The areas under the plasma concentration-time curves (AUC) of doxorubicin in rabbits with alkaline urine were approximately half the areas in rabbits with acid urine. A pharmacokinetic analysis indicated an increase in the central volume of distribution, which is interpreted as an increase in tissue permeability in the alkaline state, due to the acid-base properties of the doxorubicin molecule. The renal excretion of doxorubicin and doxorubicinol was quantitatively similar in the two groups of rabbits. The total renal excretion of anthracyclines during the experiment was calculated to approximately 6% of the administered dose. The clearances of doxorubicin were initially three times higher than inulin clearance, but approximated this value at the end of the experiment. The renal handling of doxorubicin in the rabbit is explained by glomerular filtration followed by tubular secretion and finally by a reabsorption mechanism with limited capacity.
Assuntos
Doxorrubicina/análogos & derivados , Doxorrubicina/metabolismo , Equilíbrio Ácido-Base/efeitos dos fármacos , Cloreto de Amônio/farmacologia , Animais , Bicarbonatos/farmacologia , Cromatografia Líquida de Alta Pressão , Doxorrubicina/sangue , Doxorrubicina/urina , Concentração de Íons de Hidrogênio , Injeções Intravenosas , Inulina/metabolismo , Rim/metabolismo , Cinética , Masculino , Taxa de Depuração Metabólica , Coelhos , Bicarbonato de SódioRESUMO
The doxorubicin (Adriamycin) transport was investigated in murine Ehrlich ascites tumour cells by measuring the initial rate of cellular net uptake in vitro at 37 degrees C (pH 7.3). Transport characteristics were compared with previously published data on doxorubicin transport in human red blood cells. The apparent permeability coefficient in ascites cells (2.4 X 10(-5) cm sec-1) and in red cells was of the same order of magnitude when calculated from the initial influx into cells suspended in a salt solution (37 degrees C, pH 7.3). Doxorubicin was strongly adsorbed to the cell surface of ascites cells in contrast to the doxorubicin adsorption to red cells when the cells were suspended in a salt solution. The adsorbed doxorubicin could be removed by washing the ascites cells either with DNA or with human albumin salt solutions indicating that the adsorption to cell surface components was reversible. Cell membrane modifiers, 1-alcohols, local anaesthetics, phloretin, HgCl2, para-chloromercuribenzoate, affected doxorubicin transport in ascites tumour cells and red cells in the same manner as these modifiers affected the transport of other lipophilic compounds. Ehrlich ascites tumour cells and human red blood cells appeared to represent two extremes with regard to doxorubicin adsorption to cell surfaces but doxorubicin seems to pass through the rate limiting barrier of the cell membrane by simple diffusion of the uncharged doxorubicin molecule in both cell types.
Assuntos
Carcinoma de Ehrlich/metabolismo , Doxorrubicina/metabolismo , Eritrócitos/metabolismo , 1-Octanol , 4-Cloromercuriobenzenossulfonato/farmacologia , Adsorção , Animais , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Clorpromazina/farmacologia , DNA/farmacologia , Membrana Eritrocítica/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos , Octanóis/farmacologiaRESUMO
Doxorubicin (adriamycin) forms molecular associations with other aromatic and planar molecules (hetero-association) and with other doxorubicin molecules (self-association) in aqueous solution. The ability of doxorubicin to form complexes was demonstrated in a nonbiological system by measuring the doxorubicin partition coefficient. A decreased apparent doxorubicin activity coefficient in the presence of complex formation was also demonstrated in a biological system by measuring the transmembranous doxorubicin transport and the doxorubicin distribution at equilibrium in human red blood cells and their suspending medium. Doxorubicin formed complexes in aqueous solution at 37 degrees (pH 7.3) with (a) DNA-derived bases, nucleosides, and nucleotides; (b) amino acids such as tryptophan; (c) proteins such as human serum albumin and hemoglobin; and (d) a broad range of biologically active compounds such as NAD, propanthelline, caffeine, chloroquine, imipramine, and propranolol. The apparent thermodynamic quantities of the complex formation with adenosine 5'-triphosphate were delta H0, -9.5 kcal . mole-1; delta S0, -19 eu . mole-1; and delta G0 (310 degrees K), -3.6 kcal . mole-1. The binding forces of the molecular associations were probably hydrophobic (short-range force), sometimes supported by electrostatic interaction (long-range force).