RESUMO
BACKGROUND: All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA. PURPOSE: We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes. METHODS: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer. RESULTS: The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01). CONCLUSION: Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.
Assuntos
Cetoconazol/farmacologia , Neoplasias/metabolismo , Tretinoína/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Relação Dose-Resposta a Droga , Interações Medicamentosas , Tolerância a Medicamentos , Humanos , Leucemia Promielocítica Aguda/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias/enzimologia , Tretinoína/administração & dosagemRESUMO
Cytochrome P-450 enzymes have been implicated in the oxidative catabolism of all-trans-retinoic acid (RA), a process that is accelerated by exposure to RA in cultured cells and rodents, and also in patients receiving RA as treatment for cancer (J.F.R. Muindi et al., Cancer Res., 52: 2138, 1992; Blood, 79: 299, 1992). Accelerated oxidation of RA could arise from an induction of RA-catabolizing P-450 isoforms or from an increase in oxidative cofactors. We have examined the efficiency of NADPH/O2 and lipid hydroperoxides (LOOH) to support oxidation of RA using human cell microsomes genetically enriched in different P-450 isoforms. The observed rate of RA oxidation using the NADPH/O2 system was slow for all isoforms (6-23 pmol/mg protein/min). LOOH-mediated oxidation was much faster (24-1078 pmol/mg protein/min), not isoform specific, but dependent upon the chemical nature of the LOOH. The order of efficiency of RA oxidation using LOOH was 13-hydroperoxy[S-(E,Z)]-9,11-octadecadienoic acid > 5-hydroperoxy[S-(E,Z,Z,Z)]-6,6,11,14-eicosatetraenoic acid > prostaglandin G2 > cumene hydroperoxide > tert-butylhydroperoxide > H2O2. Whereas submicromolar concentrations of 13-hydroperoxy[S-(E,Z)]- 9,11-octadecadienoic and 5-hydroperoxy[S-(E,Z,Z,Z)]-6,6,11,14- eicosatetraenoic acid oxidized RA at appreciable rates, micromolar concentrations were required for the other LOOH. These observations suggest that physiological LOOH, generated by the arachidonic acid-lipoxygenase system, may be involved in the self-induced oxidative catabolism of RA.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Isoenzimas/metabolismo , Peróxidos Lipídicos/metabolismo , Microssomos/metabolismo , Tretinoína/metabolismo , Proteínas de Transporte/análise , Proteínas de Transporte/metabolismo , Células Cultivadas , Humanos , NADP/metabolismo , Oxirredução , Receptores do Ácido RetinoicoRESUMO
Infusion of cycloheximide i.v., an antibiotic known to inhibit synthesis of protein, at a rate of 0.2 mg/kg/hr, reliably caused lysis of fever in 15 chronically febrile patients with Hodgkin's disease who did not have detectable bacterial, fungal, or viral infection. Antipyretic effects were also seen in some patients with reticulum cell sarcoma, lymphosarcoma, acute leukemia, histiocytic medullary reticulosis, plasma cell myeloma, carcinoma of the lung, and carcinoma of the cervix. The drug failed to produce defervescence in four patients with normal granulocyte reserves, who were febrile due to bacterial infection. When infused at a rate of 0.2 mg/kg/hr, the drug apparently caused an acute alteration of protein metabolism in man in that plasma amino acid nitrogen rose acutely while plasma levels of muramidase and ribonuclease fell during the period of the infusion. The data suggest that continuing synthesis of protein may be involved in nonbacterial fever of neoplastic disease. Mammalian granulocytes and monocytes are known to elaborate a pyrogenic protein following appropriate stimulation; it is suggested that in some types of neoplastic disease, particularly Hodgkin's disease, tumor cells may produce and release a pyrogenic protein and that drug-induced inhibition of its synthesis is responsible for the observed lysis of fever.
Assuntos
Cicloeximida/uso terapêutico , Febre/tratamento farmacológico , Doença de Hodgkin/complicações , Neoplasias/tratamento farmacológico , Infecções Bacterianas/complicações , Feminino , Febre/etiologia , Doença de Hodgkin/enzimologia , Humanos , Leucemia/complicações , Neoplasias Pulmonares/complicações , Doenças Linfáticas/complicações , Linfoma Difuso de Grandes Células B/complicações , Linfoma não Hodgkin/complicações , Mieloma Múltiplo/complicações , Muramidase/sangue , Proteínas de Neoplasias/biossíntese , Nitrogênio/sangue , Ribonucleases/metabolismo , Neoplasias do Colo do Útero/complicaçõesRESUMO
Cationic disc electrophoresis at pH 3.5 in 6 M urea-containing acrylamide gels permits analysis of plasma and other body fluids for the presence of trace proteins with pI greater than or equal 5 and M.W. less than 60,000. These charge and size characteristics would include rabbit and human granulocytic pyrogen, human monocytic pyrogen and, by inference, other similar candidate pyrogenic proteins. Semiquantitation of the trace protein content can be achieved by densitometric scanning of gels stained with Amido schwarz. Duplicate analyses were performed on plasma samples from 133 individuals: normal, 15; afebrile advanced cancer, 18; afebrile Hodgkin's disease, 30; febrile Hodgkin's disease, 33; other febrile lymphoma, 13; febrile advanced cancer without infection, 12; and pyogenic fever, 12. Plasma from most of the febrile patients, particularly from febrile Hodgkin's disease patients, contained trace proteins not detectable in the afebrile individuals studied. In patients with Hodgkin's disease the quantity of trace proteins present in plasma correlated well with overall severity of Hodgkin's pyrexia, but not with spontaneous hr to hr fluctuations in the fever. Marked reduction in plasma levels of the trace proteins occurred with response to antitumor therapy. Elevated plasma levels of these proteins can be induced by intratumoral inoculation of Bacillus Calmette-Guérin. They appear concomitant with the febrile response.
Assuntos
Proteínas Sanguíneas/análise , Febre/sangue , Doença de Hodgkin/sangue , Vacina BCG , Eletroforese das Proteínas Sanguíneas , Cicloeximida/farmacologia , Eletroforese Descontínua , Humanos , Concentração de Íons de Hidrogênio , Leucemia/sangue , Linfoma/sangue , Mycobacterium bovis , Neoplasias/sangue , Pirogênios/sangueRESUMO
When analyzed by cationic discontinuous electrophoresis in urea-containing polyacrylamide gels, plasma or serum from febrile individuals contains trace quanitites of five protein bands that are not recognizable in the blood of normal individuals. These proteins appear and disappear in parallel in sequential samples. Cerebrospinal fluid from febrile and nonfebrile individuals contains a protein band that is electrophoretically identical with only one of these proteins. Since the trace proteins migrate, in urea-containing polyacrylamide gel electrophoresis, as if they has molecular size of less than or equal to30,000 daltons, their absence from cerebrospinal fluid implies the existence, in vivo, of interactions between them and other serum proteins. Under nondissociating conditions, four of the bands appear to circulate in physical interaction with one another. In molecular sieve chromatography at neutral pH in lipid-free sera, the trace proteins have an approximate molecular size of 165,000 daltons; in lipemic sera they have a molecular weight of larger than or equal to200,000 daltons. Their behavior in gel filtration and in ion-exchange chromatography excludes extensive interaction with any of the following: immunoglobulin M, immunoglobulin G, alpha2-macroglobulin, haptoglobin, and albumin. Interactions between these and other serum proteins are reduced by high concentrations of urea and by low PH. The mechanisms responsible for the observed protein-protein associations would appear to include electrostatic attraction, hydrogen bonding, and weak hydrophobic interaction.
Assuntos
Febre/metabolismo , Proteínas de Neoplasias/análise , Neoplasias/metabolismo , Proteínas Sanguíneas/metabolismo , Cromatografia em Gel , Cromatografia por Troca Iônica , Eletroforese em Gel de Poliacrilamida , Humanos , Concentração de Íons de Hidrogênio , Peso Molecular , Proteínas de Neoplasias/líquido cefalorraquidiano , Ligação Proteica , UreiaRESUMO
Aclacinomycin A (ACM) is an anthracycline antibiotic recently introduced into clinical trials because of its reduced cardiac toxicity in animal models relative to Adriamycin and daunomycin. This Phase I study of ACM was conducted to determine a dose suitable for i.v. administration on an every-3-week schedule. Twenty-five adult patients with solid tumors were treated with doses of ACM ranging from 60 to 120 mg/sq m i.v. every 3 to 4 weeks. Myelosuppression was the dose-limiting toxicity, but the degree and timing of blood count depression were variable at each dose level. Nausea and vomiting were seen at myelosuppressive doses, but mucositis was rare. Alopecia was seen in approximately one-third of the patients. There was no acute cardiac toxicity, but cumulative cardiac injury could not be evaluated in this trial. There were no major objective responses in three patients who had measurable disease. The recommended doses of ACM for Phase II studies are 100 mg/sq for good-risk patients and 80 mg/sq m for patients who are heavily pretreated or who have a poor performance status.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Aclarubicina , Adulto , Idoso , Alopecia/induzido quimicamente , Antibióticos Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Hematopoese/efeitos dos fármacos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Naftacenos/administração & dosagem , Naftacenos/efeitos adversos , Náusea/induzido quimicamente , Neoplasias do Colo do Útero/tratamento farmacológicoRESUMO
Carrier-mediated influx and efflux of [3H]methotrexate by L1210 leukemia cells was inhibited by probenecid. The concentration of probenecid required for inhibition of influx was markedly greater than that required to inhibit efflux. The concentration determined for 50% inhibition of influx was 1.35 +/- 0.15 (S.D.) mM. Inhibition of this flux was competitive (Ki = 1.23 +/- 0.2 mM) and was reversed after removal of probenecid. In contrast, the concentration determined for 50% inhibition of efflux was only 0.12 +/- 0.016 mM, and inhibition was also reversed after removal of probenecid. As a consequence of the different extent of inhibition of each flux by probenecid, the level of intracellular [3H]methotrexate at steady state was markedly increased. At 0.1 and 1 mM probenecid, the steady state level was increased 2- and 2.6-fold, respectively. These observed increases are in close agreement with that expected from the effect on each flux at these concentrations. From other data on the inhibition of each flux at higher concentrations of probenecid, a maximum effect (3- to 4-fold increase) in steady-state level would be expected at a probenecid concentration between 2 and 3 mM. A similar relationship between the inhibition by probenecid of influx and efflux of [3H]methotrexate was also shown for Sarcoma 180 and Ehrlich carcinoma cells. These results have pharmacological implications with respect to the adjuvant use of probenecid or related organic ions during folate analog therapy of human cancer.
Assuntos
Metotrexato/metabolismo , Neoplasias Experimentais/metabolismo , Probenecid/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Carcinoma de Ehrlich/metabolismo , Leucemia L1210/metabolismo , Camundongos , Sarcoma Experimental/metabolismoRESUMO
Lonidamine is a potent inhibitor of spermatogenesis and a hyperthermic sensitizer. The principal established locus of biochemical action of lonidamine is a selective inhibitory effect of the energy metabolism either in NAD-linked reactions in germ cell mitochondria, as well as the glycolytic metabolism of a variety of tumor cell lines by means of inhibition of mitochondrially bound hexokinase. We carried out in vivo tumor experiments to determine whether lonidamine when combined with radiation could potentiate the cytotoxic effects of radiation on two murine tumors. The combined effects of single acute lonidamine (100 mg/kg) and single dose X-irradiation were evaluated on the transplanted methylcholanthrene-induced fibrosarcoma in BALB/c mice and on the radiation-induced fibrosarcoma in C3H/He mice. The radiosensitizing effect by lonidamine was maximal when lonidamine was administered immediately prior to or after X-irradiation. The dose modifying factor of lonidamine is estimated to be 1.36 for methylcholanthrene-induced fibrosarcoma tumors and 1.25 for radiation-induced fibrosarcoma tumors. There was no disproportionately enhanced skin reaction following the combined treatments. The present results of the potentiating effects of radiation may be attributed, in part, to the findings of cell culture studies that lonidamine is a potent inhibitor of repair of potentially lethal damage.
Assuntos
Indazóis/farmacologia , Neoplasias Experimentais/radioterapia , Pirazóis/farmacologia , Radiossensibilizantes , Animais , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Esquema de Medicação , Metabolismo Energético/efeitos dos fármacos , Indazóis/metabolismo , Taxa de Depuração Metabólica , Camundongos , Pele/efeitos da radiação , Fatores de TempoRESUMO
Cationic discontinuous electrophoresis can be carried out at pH 6.0 With excellent resolution in urea-containing acrylamide gels with potassium as the leading ion, 3-picoline as the trailing ion, and cacodylic acid as the buffer. This analytic technique has consistently demonstrated trace protein abnormalities in plasma or serum from febrile patients. It has made possible the detection of three protein bands that were obscured in similar electrophoretic assays at pH 3.8 A rough parallelism is found in the plasma (or serum) content of the five protein bands regardless of the apparent clinical cause of the febrile state.
Assuntos
Proteínas Sanguíneas/análise , Febre/sangue , Doença de Hodgkin/sangue , Infecções Bacterianas/sangue , Eletroforese das Proteínas Sanguíneas/métodos , Eletroforese Descontínua/métodos , Humanos , Concentração de Íons de Hidrogênio , Leucemia/sangue , Linfoma/sangueRESUMO
Since cancer cells produce large amounts of lactate via aerobic glycolysis and since an acidic pH has been shown to selectively enhance the cytotoxic effects of hyperthermia, we are examining the influence of cell exposure to drugs which inhibit lactate transport and lower intracellular pH upon cytotoxic effects of hyperthermia. Quercetin, a bioflavonoid that produces lactate transport inhibition, was not cytotoxic up to 4 hr at 37 degrees (0.1 mM). When HeLa cells were exposed to quercetin at 41 and 42 degrees, significant potentiation of hyperthermia-induced cytotoxicity was observed. The magnitude of the potentiation was dependent on the drug concentration, pH of the culture medium, temperature, and duration of treatment. In contrast, treatment of cells with rutin, a structurally related bioflavonoid that lacks the property of lactate transport inhibition, showed no hyperthermic potentiation.
Assuntos
Flavonoides/farmacologia , Lactatos/metabolismo , Quercetina/farmacologia , Transporte Biológico/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HeLa/efeitos dos fármacos , Células HeLa/fisiologia , Temperatura Alta , Humanos , Cinética , Ácido Láctico , Rutina/farmacologiaRESUMO
Gossypol, a polyphenolic aldehyde extracted from cotton plants, is a potent antifertility agent in humans. Since we have previously reported that several male antifertility agents including 5-thio-D-glucose and lonidamine demonstrate hyperthermic sensitizing effects in HeLa cells, we wished to determine whether gossypol also exhibits the hyperthermic sensitization. Gossypol was not cytotoxic up to 4 h at 37 degrees C (10 micrograms/ml). When HeLa cells were exposed to gossypol at 41 degrees and 42 degrees C, significant potentiation of hyperthermia induced cytotoxicity was observed. The magnitude of the potentiation was dependent on the drug concentration, pH of the culture medium, glucose concentration, temperature, and duration of treatment. The hyperthermic sensitizing effect of gossypol was increased by an acidic pH and glucose deprivation. These data suggest that the sensitizing effect of the drug may be mediated through the lowering of cellular energy level by the inhibition of both glycolysis and oxidative phosphorylation.
Assuntos
Gossipol/farmacologia , Temperatura Alta , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Glucose/deficiência , Células HeLa , HumanosRESUMO
The addition of lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of lipid peroxides in cancer patients during the course of therapy with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified conditions; the result is expressed as TBARS (thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TBARS determinations were made during the course of therapy in 17 patients, all of whom converted to "rapid" RA catabolism on therapy. An increase in plasma TBARS levels > or = 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung cancer patients treated with continuous RA therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of lipid peroxides and rapid oxidative catabolism of RA are positively correlated.
Assuntos
Peróxidos Lipídicos/sangue , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Tretinoína/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Peróxidos Lipídicos/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/tratamento farmacológico , Valores de Referência , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Tretinoína/uso terapêuticoRESUMO
5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Ácido Aspártico/análogos & derivados , Carcinoma/tratamento farmacológico , Compostos Organofosforados/administração & dosagem , Ácido Fosfonoacéticos/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Ácido Aspártico/administração & dosagem , Ácido Aspártico/efeitos adversos , Contagem de Células Sanguíneas , Esquema de Medicação , Avaliação de Medicamentos , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Gastroenteropatias/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Orótico/urina , Ácido Fosfonoacéticos/efeitos adversos , Ácido Fosfonoacéticos/análogos & derivados , Pirimidinas/biossínteseRESUMO
Although clinical trials of high-dose methotrexate (MTX) sequenced before 5-fluorouracil (FUra) with leucovorin (LV) rescue apparently have resulted in increased numbers of tumor responses, this increased antitumor activity often has been accompanied with toxicity. The present report describes an attempt to improve therapeutic results with this drug combination by appropriate metabolic modulation in the preclinical BALB/c X DBA/8 F1 murine breast tumor model. A LV rescue schedule consisting of 300 mg/kg administered at 4.5 and 19.5 hr after high-dose MTX (300 mg/kg/week for 3 weeks) prevented MTX toxicity. When FUra was administered 2.5 hr after MTX (with LV rescue), the dose of FUra had to be decreased, and we could not obtain convincing evidence for a differential cytotoxic effect on tumor versus normal host tissue. However, when a delayed uridine rescue schedule was added to protect the host from the toxic activity of FUra, the FUra dose could be increased even in the presence of high-dose MTX, and the therapeutic result was enhanced significantly without an increase in host toxicity. Finally, it was possible to add N-phosphonacetyl-L-aspartate to this drug combination (in the appropriate sequence: N-phosphonacetyl-L-aspartate before high-dose MTX-before high-dose FUra, followed by double rescue with LV and uridine) without producing increased toxicity to yield a significant increase in partial tumor regression rate. The biochemical rationale for the selection and sequence of administration of these agents is discussed.
Assuntos
Antineoplásicos , Ácido Aspártico/análogos & derivados , Fluoruracila/administração & dosagem , Metotrexato/administração & dosagem , Compostos Organofosforados/uso terapêutico , Ácido Fosfonoacéticos/uso terapêutico , Animais , Ácido Aspártico/uso terapêutico , Quimioterapia Combinada , Feminino , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Ácido Fosfonoacéticos/análogos & derivados , Uridina/uso terapêuticoRESUMO
Because of the association between the incorporation of 5-fluorouracil (FUra) into RNA and cytotoxicity, uridine was examined for potential selective reduction of host toxicity. Male BALB/c x DBA/2 F1 mice (tumor free or bearing advanced colon tumor 26) were used. Two uridine schedules (each beginning 2 hr after FUra) have been successful: (a) uridine at 800 mg/kg every 2 hr for three doses followed 18 hr later by uridine at 800 mg/kg every 2 hr for four doses; or (b) two doses of uridine at 3500 mg/kg separated by an 18-hr interval. With two doses of uridine at 3500 mg/kg, the 50% lethal dose for a single dose of FUra in tumor-free mice was increased 68% from 190 to 320 mg/kg. White blood cell levels were depressed 67% after a single dose of FUra at 200 mg/kg, whereas white blood cells were depressed by only 39% when the same dose of FUra was followed by uridine rescue. In tumor-bearing mice, uridine rescue reduced FUra-induced host toxicity without significant loss of antitumor activity. Even more striking results were obtained with a combination containing N-(phosphonacetyl)-L-aspartate (200 mg/kg) and 6-methylmercaptopurine riboside (25 mg/kg), administered 24 hr before FUra. In this drug combination, the maximum tolerated dose of FUra is 40 mg/kg on a weekly schedule. With uridine rescue, FUra can be doubled to 80 mg/kg without increasing toxicity, resulting in significantly improved antitumor activity. Examination of the effect of uridine rescue on the incorporation of FUra into RNA and the subsequent recovery from inhibition of DNA synthesis in bone marrow versus tumor revealed that the uridine rescue schedule resulted in relatively faster clearance of FUra from RNA of both tissues but a striking enhancement of the rate of recovery of DNA synthesis only in the bone marrow.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Uridina/uso terapêutico , Animais , Fluoruracila/efeitos adversos , Cinética , Leucopenia/etiologia , Leucopenia/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Uridina/sangueRESUMO
Doses of N-(phosphonacetyl)-L-aspartic acid (PALA) lower than those required for therapeutic activity against the spontaneous murine breast tumor (BALB/c X DBA/8 F1) were found to produce significant depression in uridine triphosphate pools in the tumor. Using such low, nontherapeutic, but biochemically active doses of PALA in combination with 5-fluorouracil (FUra(, it was possible to maintain the dose of FUra at its full maximum tolerated single agent dose. In comparison with the maximum tolerated dose of FUra alone, the combination of FUra plus low-dose PALA produced a significant increase in the level of tumor FUra-containing RNA, only a slight increase in intestinal FUra-containing RNA, and no increase in bone marrow FUra-containing RNA. These biochemical results correlated with the therapeutic findings of significantly increased antitumor activity without an increase in host toxicity. A review of currently reported PALA plus FUra clinical protocols reveals that the experimental parameters which have produced successful therapeutic results in the laboratory (i.e., a low-PALA:high-FUra dosage ratio) have not yet been translated into clinical trial. Final judgment on the clinical efficacy of PALA:FUra combinations must await the results of proposed low-PALA:high-FUra clinical trials.
Assuntos
Ácido Aspártico/análogos & derivados , Fluoruracila/administração & dosagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Compostos Organofosforados/administração & dosagem , Ácido Fosfonoacéticos/administração & dosagem , Animais , Ácido Aspártico/administração & dosagem , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Ácido Fosfonoacéticos/análogos & derivados , RNA/metabolismoRESUMO
To investigate the mechanism of cis-diamminedichloroplatinum(II) (cisplatin) nephrotoxicity, male Sprague-Dawley rats were given one injection of cisplatin (6 mg/kg i.v.). Urinary levels of amino acids and gamma-glutamyl transpeptidase were monitored for 8 days; kidney homogenate content of gamma-glutamyl transpeptidase was followed for 50 hr, and that of selenium-dependent glutathione peroxidase and total glutathione was followed for 4 hr. Peak urinary levels of amino acids and gamma-glutamyl transpeptidase occurred 4.5 hr after the i.v. dose. Glutamine, glycine, and ethanolamine were all elevated greater than 20 times that of the control at 4.5 hr and were still significantly elevated at 50 hr. Total renal glutathione content increased 51 +/- 17% (S.D.) of control values 20 min after cisplatin was given, before returning to base-line levels. No depletion of either renal glutathione or glutathione peroxidase was detected over the time interval studied. These results demonstrate an earlier physiological impairment than has hitherto been shown. Furthermore, depletion of glutathione and glutathione peroxidase does not occur in the rat kidney following therapeutic doses of cisplatin, in contrast to the changes observed in cardiac tissue following doxorubicin treatment.
Assuntos
Aciltransferases/metabolismo , Cisplatino/toxicidade , Glutationa/metabolismo , Rim/patologia , Aciltransferases/urina , Aminoácidos/urina , Animais , Glutationa Peroxidase/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos , TransglutaminasesRESUMO
We have carried out a clinical trial in which patients with relapsed leukemia were treated with thymidine (dThd) prior to and concomitantly with the administration of 1-beta-D-arabinofuranosylcytosine (ara-C) in an effort to kinetically and biochemically modulate the leukemic cells with two objectives: (a) to increase the S-phase fraction before giving ara-C; and (b) to increase the uptake and phosphorylation of ara-C. Six patients with acute nonlymphocytic leukemia who had relapsed after conventional or experimental therapy were given continuous i.v. infusions of dThd in conjunction with ara-C. dThd was started at 75 g/sq m/day (producing 1 mM plasma levels) and was given for 5 to 8 days until the proportion of bone marrow cells in S-phase (measured by autoradiography and flow cytometry) had increased and/or stabilized; then ara-C at 200 mg/sq m/day was begun. Twenty-four hr after initiation of ara-C therapy, the dThd dose was reduced to 30 g/sq m/day (plasma dThd, 0.1 to 0.6 mM). Both drugs were continued for 6 to 12 days until marrow aplasia or unacceptable toxicity occurred. Four patients with a base-line labeling index lower than 30% experienced a sustained increase in the S-phase fraction; two patients with a base-line labeling index higher than 30% experienced a reduction in the S-phase compartment during dThd infusion, in one case followed by an increase. The degree of S-phase arrest did not correlate with remission induction. In 5 patients, the flash incorporation of labeled ara-C into nucleoside triphosphate and deoxycytidine into DNA of bone marrow cells was measured. Three patients had a significant increase in the incorporation of deoxycytidine into DNA. Two of them achieved a complete remission. Increases in ara-C uptake were less impressive. A new technique was used to measure the absolute number of blasts present in the bone marrow. A decrease in leukemic cells between 0.9 and 2.6 logs10/mm was found at the end of the infusions. Three patients experienced greater than 2-log reduction. Two of them entered complete remission that lasted 6 weeks and 3 months, respectively. These correlations should be interpreted with caution because of the small number of patients treated. This study suggests that dThd, although of very limited therapeutic value by itself, may have potentiated the antitumor activity of ara-C to some extent. Whether this effect is of significance can only be determined by further studies.
Assuntos
Citarabina/uso terapêutico , Leucemia/tratamento farmacológico , Timidina/uso terapêutico , Doença Aguda , Adulto , Citarabina/metabolismo , Desoxicitidina/metabolismo , Feminino , Humanos , Interfase/efeitos dos fármacos , Cinética , Masculino , Pessoa de Meia-Idade , FosforilaçãoRESUMO
Patients with acute leukemia in relapse were given 5'-(9-acridinylamino)methanesulfon-m-anisidide at a dosage of 75 to 200 mg/sq m as a daily bolus infusion of 5 consecutive days. None of the 11 patients treated at 75 to 150 mg/sq m daily for 5 days achieved remission. Ten patients with acute lymphoblastic leukemia and 21 with acute nonlymphoblastic leukemia were given treatment at 200 mg/sq m daily for 5 days. Six of these patients achieved complete remission, three with acute lymphoblastic leukemia and three with acute nonlymphoblastic leukemia. Neutropenia and thrombocytopenia were seen in all patients and in the responders lasted a median of 39 and 41 days, respectively. Stomatitis was the most significant nonhematopoietic toxicity noted. occurring in 80% of the patients. Hyperbilirubinemia was seen in 25% of the patients treated. Since 4'-(9-acridinylamino)methanesulfon-m-anisidide will induce remission in heavily pretreated patients with acute leukemia, consideration should be given to exploring its use in combination with other active drugs.
Assuntos
Aminoacridinas/administração & dosagem , Leucemia/tratamento farmacológico , Adolescente , Adulto , Aminoacridinas/efeitos adversos , Amsacrina , Esquema de Medicação , Avaliação de Medicamentos , Humanos , Hiperbilirrubinemia/etiologia , Leucemia Linfoide/tratamento farmacológico , Pessoa de Meia-Idade , Neutropenia/etiologia , Pancitopenia/etiologia , Estomatite/etiologia , Trombocitopenia/etiologiaRESUMO
We have treated 33 patients with different types of advanced cancer by 10-day continuous i.v. infusion courses of hexamethylene bisacetamide (HMBA), a drug that produces differentiation of a variety of transformed cell lines on prolonged exposure in vitro to drug concentrations of 3 to 5 mM. In this dose-finding and pharmacokinetic study, five dosage levels were explored from 12 to 28 g/m2/day. Patients who had not shown progression of disease were given repeat courses of therapy at 28-day intervals. Seventy-two courses of therapy were administered; 17 patients received one course; eight patients received two; six patients received three; and one patient each received four and 17+ courses, respectively. The maximal tolerated dose was 28 g/m2/day for 10 days; the dose-limiting toxic effects were thrombocytopenia with hemorrhage and central nervous system dysfunction manifesting as disorientation and confusion. Based on these studies the recommended dosage for Phase II studies by the 10-day schedule is 24 g/m2/day. Pharmacokinetic studies demonstrated rapid clearance of HMBA from plasma; the decay phase data fit a one compartment model with a mean plasma half-life of 2.5 h and a range from 0.6 to 5.8 h. Mean plasma steady-state levels in our patients were 0.37, 0.58, 0.86, 0.88, and 1.42 mM, at the 12-, 16-, 20-, 24-, and 28-g/m2/day dosage levels, respectively. The data indicate that plasma HMBA concentrations of 1 mM can be maintained for 10 days with acceptable patient tolerance, but that HMBA concentrations in excess of 1.4 mM for 10 days are associated with substantial hematological and central nervous system toxicity. Objective antitumor effects were observed in five patients; one woman with non-small cell lung cancer, who has received 17+ courses over a period of 28+ mo, achieved a partial remission that continues at 28+ mo on therapy. Transient regression of cutaneous metastases was observed in three patients with breast carcinoma and one patient with colorectal carcinoma.