RESUMO
BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Éteres Cíclicos/uso terapêutico , Macrolídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Éteres Cíclicos/administração & dosagem , Éteres Cíclicos/efeitos adversos , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Pessoa de Meia-Idade , Adulto JovemRESUMO
The replication of Sarcoma 180 cells in culture was inhibited by 3,6-dihydroxy-4,5-dimethylphthalaldehyde (HMPA). The inhibition of growth caused by HMPA was evident after treatment of cells with drug for only 15 min. This exposure period caused decreased in (a) cloning efficiency, (b) transport and/or phosphorylation of [3H]thymidine and [3H]uridine, (c) incorporation of radioactive nucleosides into acid-insoluble material, and (d) incorporation of [3H]leucine into protein. Examination of the cytotoxicities of the model compounds 2,3,5,6-tetramethyl-1,4-dihydroquinone (durohydroquinone) and o-phthalaldehyde indicated that the dialdehyde portion of the molecule was responsible for the cytocidal effects of HMPA. The ratio of adenosine triphosphate to adenosine diphosphate in the acid-soluble fraction of Sarcoma 180 cells incubated in vitro with HMPA for 45 min was reduced in a concentration-dependent manner. The reduction in the ATP pool size produced by HMPA contrasts with the action of the periodate oxidation product of cytidine dialdehyde, which has been reported to increase the intracellular concentration of adenosine triphosphate.
Assuntos
Trifosfato de Adenosina/metabolismo , Aldeídos/farmacologia , Antineoplásicos/farmacologia , Sarcoma Experimental/metabolismo , o-Ftalaldeído/farmacologia , Nucleotídeos de Adenina/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Camundongos , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/biossíntese , o-Ftalaldeído/análogos & derivadosRESUMO
Eleven patients treated with a 5.5-day continuous i.v. infusion of 500 mg/m2/day of (6R,S)-folinic acid in combination with daily bolus 5-fluorouracil had a median steady-state plasma concentration of 3.25 microM (6S)-folinic acid (the bioactive diastereoisomer). The bioactive metabolite (6S)-5-methyltetrahydrofolic acid, analyzed in six patients, reached a median steady-state plasma concentration of 5.7 microM. The lowest plasma concentrations at steady-state were 1.86 microM (6S)-folinic acid and 3.12 microM (6S)-5-methyltetrahydrofolic acid. These concentrations are above the minimum concentrations shown by other investigators to produce synergism between (6R,S)-folinic acid and 5-fluorouracil in vitro. The median steady-state plasma concentration of (6R)-folinic acid was 38.2 microM, more than 10 times the concentration of (6S)-folinic acid. Along with other plasma pharmacokinetic parameters, terminal half-lives were estimated for (6S)-folinic acid (median, 45.4 min), (6R)-folinic acid (median, 388 min), and (6S)-5-methyltetrahydrofolic acid (median, 446 min). Investigation of the renal pharmacokinetics confirmed the marked difference in the renal clearance of the two diastereoisomers of folinic acid which had been observed after low doses of (6R,S)-folinic acid (J. A. Straw, D. Szapary, and W. T. Wynn, Cancer Res., 44: 3114-3119, 1984). However, the low renal clearance of (6R)-folinic acid (median, 8.2 ml/min/m2) was attributable to the extensive binding of (6R)-folinic acid to plasma proteins (median, 8.7% free), not to reabsorption in the kidney.
Assuntos
Leucovorina/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Fluoruracila/farmacocinética , Humanos , Infusões Intravenosas , Rim/metabolismo , Leucovorina/administração & dosagem , Taxa de Depuração Metabólica , Ligação Proteica , Estereoisomerismo , Tetra-Hidrofolatos/metabolismoRESUMO
The effects of amino acid deprivation and treatment with amino alcohols upon the growth, viability, and susceptibility to methotrexate (MTX) cytotoxicity were examined in BALB/3T3 cells and their virally transformed counterparts, SV-T2 cells. Cells were deprived of either histidine or tyrosine plus phenylalanine, or they were treated with amino alcohol analogues of histidine and tyrosine (histidinol and tyrosinol). When incubated in medium lacking histidine and supplemented with dialyzed serum (histidine-deficient medium), the BALB/3T3 cells remained viable for at least 3 days, but they ceased logarithmic growth, and the cell number reached an early plateau. In contrast, the SV-T2 cells continued to divide in histidine-deficient medium. Neither cell line ceased division in medium deficient in both phenylalanine and tyrosine. Incubation of the BALB/3T3 cells with 1.5 mM histidinol or 1.0 mM tyrosinol caused an early plateau similar to the effect of histidine deprivation. SV-T2 cells were not affected by these concentrations of histidinol or tyrosinol, but growth was arrested at higher concentrations. Any of the conditions used which caused a plateau in the number of BALB/3T3 cells substantially protected the treated cells from cell death caused by MTX. Therefore, pretreatment of BALB/3T3 cells with histidine deprivation, 1.5 mM histidinol, or 1.0 mM tyrosinol protected this cell line against MTX-induced cell death, while the same pretreatment conditions failed to protect SV-T2 cells. (SV-T2 cells were protected by 4.0 mM histidinol.) Thus, the ability of MTX to kill cells in vitro can be selectively modified by conditions which protect cells which retain normal growth control characteristics, but which do not protect virally transformed cells.
Assuntos
Histidina/deficiência , Histidinol/farmacologia , Imidazóis/farmacologia , Metotrexato/farmacologia , Tirosina/análogos & derivados , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Fenilalanina/deficiência , Tirosina/deficiência , Tirosina/farmacologiaRESUMO
Because of the synergy seen in adult trials when 5-fluorouracil is combined with leucovorin, we initiated a Phase I trial of this combination in children's refractory cancer. Leucovorin, an equal mixture of the (6R,S)-diastereoisomers, was administered p.o. for 6 consecutive days as 4 equal doses at 0, 1, 2, and 3 h totaling 500 mg/m2/day. 5-Fluorouracil was given daily on days 2 to 6 as an i.v. bolus immediately following the last dose of leucovorin. The leucovorin dose was held constant while the 5-fluorouracil dose was escalated in cohorts of patients from 300 mg/m2/day to its maximally tolerated dose. Thirty-five patients (19 with acute leukemia and 16 with solid tumors) were evaluable for toxicity. The maximally tolerated dose of FUra was 450 mg/m2/day for 5 treatments for patients with solid tumors and 650 mg/m2/day for 5 treatments for the children with leukemia. The dose-limiting toxicities were myelosuppression and stomatitis. Other side effects included transient, mild elevations of serum transaminases, mild nausea, vomiting, and diarrhea. The pharmacokinetics of high-dose p.o. leucovorin was studied in 23 children. There was considerable interpatient variability in the plasma concentrations of total bioactive folates (TBAF), (6S)-leucovorin, and (6S)-5-methyltetrahydrofolic acid. The maximum plasma concentration (Cmax) of TBAF was 821 +/- 97 (SE) nM, occurring at a median of 8 h; the Cmax of (6S)-leucovorin was 77 +/- 11 nM, occurring at 4 h. The TBAF concentration fell to 146 +/- 42 nM by 24 h. (6S)-5-Methyltetrahydrofolic acid accounted for 90 +/- 7% of the TBAF at the Cmax. The plasma concentration of (6R)-leucovorin, the unnatural isomer, was equal to that of TBAF. Thus, p.o. leucovorin reduced the 5-fold excess of (6R)-leucovorin over TBAF seen after i.v. doses. The relative amounts of the three major plasma species were approximately the same as in adults, even though the Cmax of each compound was lower.
Assuntos
Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Avaliação de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Fluoruracila/toxicidade , Humanos , Lactente , Leucovorina/farmacocinética , Leucovorina/toxicidade , Masculino , Neoplasias/metabolismo , Estereoisomerismo , Tetra-Hidrofolatos/metabolismo , Tetra-Hidrofolatos/toxicidadeRESUMO
Twenty-seven patients with advanced cancer were entered in a phase I study of bolus i.v. 5-fluorouracil at a dose of 370 mg/m2/day for 5 days combined with a continuous i.v. infusion of (6S)-folinic acid for 5.5 days, starting 24 h in advance of the first 5-fluorouracil dose. The dose of (6S)-folinic acid was escalated in cohorts of patients from 250 mg/m2/day to a maximum of 1000 mg/m2/day. The pharmacokinetics of (6S)-folinic acid were studied in the 3 patients given 250 mg/m2/day and in 6 patients given 1000 mg/m2/day. The mean steady-state plasma concentrations of (6S)-folinic acid and its principal metabolite (6S)-5-methyltetrahydrofolate at the 250 mg/m2/day dose were 2.7 and 5.1 microM, respectively. Both concentrations were comparable to the concentrations produced when (6S)-folinic acid was administered as half of a (6R,S)-folinic acid mixture (E. M. Newman et al., Cancer Res., 49:5755-5760, 1989). At the 1000 mg/m2/day dose of (6S)-folinic acid, the concentration of (6S)-folinic acid was 15.3 microM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 microM. The change in the ratio of the parent compound to its metabolite was accounted for by a decrease in the nonrenal clearance of (6S)-folinic acid, probably indicating saturation of its metabolism. The toxicities observed in this phase I trial, including stomatitis, diarrhea, neutropenia, and anemia, did not differ in nature or severity from those produced by 5-fluorouracil and (6R,S)-folinic acid when administered on the same schedule. Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested.
Assuntos
Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias/metabolismo , Adulto , Idoso , Esquema de Medicação , Avaliação de Medicamentos , Sinergismo Farmacológico , Feminino , Fluoruracila/farmacocinética , Humanos , Infusões Intravenosas , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológicoRESUMO
In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.
Assuntos
Antídotos/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Idoxuridina/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Antígeno Ca-125/sangue , DNA de Neoplasias/metabolismo , Esquema de Medicação , Quimioterapia Combinada , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Idoxuridina/efeitos adversos , Idoxuridina/farmacocinética , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/sangueRESUMO
Lometrexol inhibits the first folate-dependent enzyme in de novo purine biosynthesis and is avidly polyglutamated and retained in tissues expressing folylpolyglutamate synthetase. Although clinical studies have been limited by cumulative toxicity, preclinical studies show that pretreatment with folic acid can protect normal tissue while maintaining tumor cytotoxicity. Therefore, a Phase I study of lometrexol every 21 days preceded by i.v. folic acid was initiated. Lometrexol was studied in six patients at 15 mg/m2, in six patients at 20 mg/m2, in three patients at 25 mg/m2, and in nine patients at 30 mg/m2. Patients received either 5 mg of folic acid 1 h before or 25 mg/m2 3 h before lometrexol. Blood samples were obtained around the first course and weekly thereafter for determination of plasma and erythrocyte (RBC) lometrexol concentrations. Bioactive folates in plasma and RBCs were determined in a subset of patients. Lometrexol pharmacokinetics were best described by a three-compartment model. Mean clearance and volume of distribution were 1.6 +/- 0.6 liters/h/m2 and 8.9 +/- 4.1 liters/m2. Mean half-lives were 0.23 +/- 0.1, 2.9 +/- 1.4, and 25.0 +/- 48.7 h. Pharmacokinetics were independent of either lometrexol or folic acid dose. In the weekly blood samples, RBC lometrexol levels rose, long after plasma lometrexol was undetectable. RBC lometrexol levels were independent of folic acid or lometrexol dose. Bioactive folates measured in plasma and RBCs during this same time period did not accumulate. Rising RBC levels were correlated with a fall in hematocrit, hemoglobin, and platelet count. This study indicates that the cumulative toxicity of lometrexol is related to tissue concentration and not plasma pharmacokinetics. RBC lometrexol may be an indicator of cumulative drug exposure and effect.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Sangue/efeitos dos fármacos , Eritrócitos/metabolismo , Antagonistas do Ácido Fólico/farmacocinética , Tetra-Hidrofolatos/farmacocinética , Ácido Fólico/sangue , Humanos , Metotrexato/efeitos adversos , Tetra-Hidrofolatos/efeitos adversosRESUMO
The pharmacokinetics of etoposide at doses of 1 gm/m2 to 3 gm/m2 were studied in patients with hematologic malignancies. The noncompartmental systemic clearance, mean residence time, steady-state volume of distribution, and elimination half-life were independent of the dose of etoposide, whereas the AUC was proportional to the dose. Comparison of these results with those reported previously indicates that etoposide exhibits linear pharmacokinetics over a thirtyfold range in doses (0.1 to 3 gm/m2).
Assuntos
Etoposídeo/farmacocinética , Alanina Transaminase/sangue , Transplante de Medula Óssea , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Humanos , Taxa de Depuração MetabólicaRESUMO
A number of hydroquinone dialdehydes and structurally related compounds were synthesized and tested for antineoplastic efficacy against transplanted murine tumors. 3,6-Dihydroxy-4,5-dimethylphthalaldehyde,3,6-dihydroxy-4,5-dipropylphthalaldehyde, and 3,6-dihydroxy-4,5-dimethylphthalaldehyde hemialdal tetraacetate significantly prolonged the survival time of mice bearing either Sarcoma 180, Ehrlich carcinoma, or adenocarcinoma 755 ascites tumors. In addition, these agents were cytotoxic to Sarcoma 180 cells in culture at concentrations in the range of 25-30 microM.
Assuntos
Aldeídos/síntese química , Antineoplásicos/síntese química , Aldeídos/farmacologia , Animais , Feminino , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Camundongos , Camundongos Endogâmicos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Sarcoma 180/tratamento farmacológico , Relação Estrutura-Atividade , o-Ftalaldeído/análogos & derivados , o-Ftalaldeído/farmacologiaRESUMO
Some properties of the human ovarian carcinoma line A2780 and a subline three times more resistant than the parent line to cisplatin are compared in this report. The rates of uptake and release of cisplatin were similar in the two cell lines. Resistance to cisplatin was associated with: (a) cross-resistance to 5-fluorouracil and methotrexate; (b) a 2.5-fold increase in thymidylate synthase, as measured by both enzyme activity and the capacity to complex 5-fluorodeoxyuridylate; and (c) an increase in the intracellular pools of 5,10-methylenetetrahydrofolate and tetrahydrofolate. These data suggest that cross-resistance to 5-fluorouracil and methotrexate in A2780 cells may be a consequence of increases in their respective target enzymes.
Assuntos
Cisplatino/farmacologia , Fluoruracila/farmacologia , Metotrexato/farmacologia , Células Tumorais Cultivadas/citologia , Transporte Biológico , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Cisplatino/metabolismo , Resistência a Medicamentos , Feminino , Fluoruracila/metabolismo , Humanos , Metotrexato/metabolismo , Neoplasias Ovarianas , Timidilato Sintase/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Children with acute lymphocytic leukemia (ALL) in remission were treated with overlapping sequential infusions of methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (araC) as part of continuation therapy. The doses and the sequence were chosen to mimic conditions that produced greater than additive antineoplastic activity with these two drugs in preclinical studies. To assess the potential for the drug combination to exhibit greater than additive effect in vivo, we investigated several biochemical parameters that had been associated with synergism in vitro. Because the patients were in remission, the intracellular parameters could only be measured in cytologically normal hematopoietic cells. We observed that (1) the mean plasma concentrations of MTX and araC were above those required to obtain a greater than additive cytotoxicity with the two drugs in tissue culture; (2) MTX did not have a significant antipurine effect in bone marrow mononuclear cells; (3) the mean intracellular concentration of deoxycytidine triphosphate (dCTP) was significantly lower after treatment with the drug combination than after therapy with araC alone; and (4) the ratio of araC triphosphate (araCTP) to dCTP was 2.6 times higher after treatment with the combination than after araC alone. These results indicate that it is possible to achieve in patients the biochemical conditions associated with the greater than additive antineoplastic activity of MTX and araC in vitro.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Metotrexato/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Medula Óssea/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Criança , Citarabina/administração & dosagem , DNA de Neoplasias/biossíntese , Avaliação de Medicamentos , Sinergismo Farmacológico , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucovorina/administração & dosagem , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de RemissãoRESUMO
PURPOSE: To identify a dose of the demethylating agent 5-aza-2'-deoxycytidine (DAC) with acceptable side effects, and to study its effect on the methylation patterns of relevant genes in tumor biopsies before and after treatment with a novel methylation assay using real-time PCR. METHODS: A group of 19 patients with metastatic solid tumors were treated with DAC by continuous intravenous infusion over 72 h, days 1-3 of a 28-day cycle. Tumor biopsies were taken before and 7 days after starting DAC. RESULTS: The dose levels studied were 20, 30 and 40 mg/m(2). Grade 4 neutropenia was found in two of five patients at 40 mg/m(2) and one of six patients at 30 mg/m(2). No objective responses were seen in this study. Steady-state DAC levels of 0.1 to 0.2 microM were achieved in the 30 and 40 mg/m(2) cohorts. Changes in methylation were observed, but no single gene consistently demonstrated evidence of demethylation. CONCLUSIONS: DAC was tolerated at a dose of 30 mg/m(2) per day for a 72-h intravenous infusion. Changes in gene methylation were observed.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/análogos & derivados , Azacitidina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/administração & dosagem , Azacitidina/farmacologia , Biópsia , DNA de Neoplasias , Decitabina , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Reação em Cadeia da PolimeraseRESUMO
Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácido Aspártico/administração & dosagem , Ácido Aspártico/análogos & derivados , Diarreia/induzido quimicamente , Sistema Digestório/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Ácido Fólico/sangue , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Ácido Fosfonoacéticos/administração & dosagem , Ácido Fosfonoacéticos/análogos & derivados , Modelos de Riscos Proporcionais , Pirimidinas/biossíntese , Indução de Remissão , Fatores de Risco , Timidilato Sintase/antagonistas & inibidoresRESUMO
PURPOSE: To evaluate the pharmacokinetics and toxicity of high-dose intravenous (i.v.) methotrexate (MTX) with leucovorin in patients with meningeal carcinomatosis. METHODS: Of 16 eligible patients entered on this study, 13 with meningeal carcinomatosis from breast cancer, lung cancer, or osteosarcoma were treated with MTX at loading doses of 200-1500 mg/m2, followed by a 23-h infusion of 800-6000 mg/m2. Three patients without meningeal disease were also treated and the cerebrospinal fluid (CSF) MTX concentrations were compared in patients with and without central nervous system (CNS) disease. RESULTS: Patients without CNS disease had lower CSF MTX concentrations relative to the plasma MTX levels than those with CNS disease, who all had CSF MTX concentrations above the target cytotoxic concentration (1 microM). The CSF MTX concentrations correlated better with the free and the total plasma MTX concentrations than with the doses. The mean half-life of CSF MTX was 8.7 +/- 3.4 h. The mean plasma clearance of MTX was not significantly different in patients with CNS disease (84 +/- 41 ml/min per m2) versus without CNS disease (59 +/- 38 ml/min per m2). All toxicities were grade 2 or less except grade 3 hematologic toxicity. No patient had an objective response in the CSF. CONCLUSION: This trial demonstrates that potentially cytotoxic CSF MTX concentrations (> 1 microM) are delivered safely by i.v. infusion, a less invasive and better distributed CSF therapy compared with intrathecal MTX. Because of the excellent pharmacokinetics and toxicity, high-dose i.v. MTX should be evaluated at a loading dose of 700 mg/m2 and a 23-h infusion of 2800 mg/m2 with leucovorin in less heavily pretreated patients with carcinomatous meningitis.
Assuntos
Neoplasias Meníngeas/tratamento farmacológico , Metotrexato/farmacocinética , Adulto , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucovorina/uso terapêutico , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/secundário , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/líquido cefalorraquidiano , Metástase Neoplásica , Osteossarcoma/patologiaRESUMO
A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/ m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P < 0.0001). The mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 microM at 1, 2 and 3.2 g/m2 per day, respectively. The mean +/- SE renal and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The steady-state concentration of hydroxyurea was > 200 microM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.
Assuntos
Antineoplásicos/farmacocinética , Hidroxiureia/farmacocinética , Neoplasias/metabolismo , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Humanos , Hidroxiureia/administração & dosagem , Hidroxiureia/efeitos adversos , Infusões Intravenosas , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamenteAssuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antagonistas do Ácido Fólico/efeitos adversos , Ácido Fólico/uso terapêutico , Pancitopenia/prevenção & controle , Estomatite/prevenção & controle , Tetra-Hidrofolatos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Esquema de Medicação , Feminino , Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Neoplasias/tratamento farmacológico , Pancitopenia/induzido quimicamente , Estomatite/induzido quimicamente , Tetra-Hidrofolatos/farmacocinética , Falha de TratamentoRESUMO
Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.