RESUMO
The effects of imatinib are partly mediated by the inhibition of platelet-derived growth factor (PDGF), which is highly expressed in the liver. In this phase-I/II trial pharmacokinetic parameters of imatinib given for hepatocellular cancer were similar to those previously derived from CML patients. The AUC of N-desmethyl-imatinib depended on liver function; the metabolism of imatinib was otherwise comparable to other populations. During short-termed imatinib treatment (4 weeks, 400 mg/d), plasma PDGF significantly decreased. The AUC of N-desmethyl-imatinib could best be attributed to the pharmacodynamic effect of PDGF inhibition (r=-0.679 [95% CI: -0.917 to -0.0868], p=0.031).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Fígado/metabolismo , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Becaplermina , Benzamidas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Mesilato de Imatinib , Fígado/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Octreotida/administração & dosagem , Piperazinas/administração & dosagem , Piperazinas/sangue , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Proteínas Proto-Oncogênicas c-sis , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
As low trough levels of mycophenolic acid (MPA) have been measured in recipients of allo-SCTs, we performed a pilot study targeting mycophenolate mofetil (MMF) doses according to the MPA area under the concentration (AUC) levels. Twenty-nine patients were transplanted from matched sibling (n=7) and unrelated donors (n=22). Tacrolimus was given orally from day -1 to achieve trough blood levels of 5-10 ng/ml. MMF was started on day 0 at 1500 mg intravenously b.i.d. AUC measurements of MPA by HPLC were scheduled on days 3, 7 and 11 after transplantation. The MMF dose was modified to achieve an MPA AUC of 35-60 microg/ml/h. With the respective adjustments 66 and 75% surpassed the lower AUC target on days 7 and 11, respectively. The cumulative incidence of grade III-IV acute GVHD was 28% (8/29). Eight out of 24 evaluable patients (33%) suffer from limited (n=3) or extensive (n=5) chronic GVHD. Overall, the results of this study suggest that targeting of MPA exposure is feasible early after transplantation. A simplified MMF targeting strategy based on MPA C(max) or C(2h) levels seems to be warranted in future trials involving more patients at later time points in the outpatient setting.
Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Ácido Micofenólico/análogos & derivados , Adulto , Idoso , Área Sob a Curva , Monitoramento de Medicamentos , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/farmacocinética , Ácido Micofenólico/uso terapêutico , Transplante HomólogoRESUMO
OBJECTIVES: Recent data show that Imatinib mesylate (IM) also affects haematopoietic stem cells (HSC), T lymphocytes and dendritic cells that do not harbour constitutively active tyrosine kinases. MATERIALS AND METHODS: We evaluated possible effects of IM on human bone marrow-derived mesenchymal stem cells (MSC) in vitro. RESULTS: Screening the activity of 42 receptor tyrosine kinases revealed an exclusive inhibition of platelet-derived growth factor receptorbeta (PDGFRbeta). Analysis of downstream targets of PDGFRbeta demonstrated IM-mediated reduction of Akt and Erk1/2 phosphorylation. Culture of MSC with IM led to the reversible development of perinuclear multi-vesicular bodies. The proliferation and clonogenicity of MSC were significantly reduced compared to control cultures. IM favoured adipogenic differentiation of MSC whereas osteogenesis was suppressed. The functional deficits described led to a 50% reduction in the support of clonogenic haematopoietic stem cells, cultured for 1 month on a monolayer of MSC with IM. CONCLUSION: In summary, inhibition of PDGFRbeta and downstream Akt and Erk signalling by IM has a significant impact on proliferation and differentiation of human MSC in vitro.
Assuntos
Antineoplásicos/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Adipócitos/citologia , Benzamidas , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Clonais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Mesilato de Imatinib , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteócitos/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
Fludarabine is commonly used in combination with busulfan as part of conditioning regimens before allogeneic stem cell transplantation. So far, no data are available on busulfan-fludarabine drug interactions in transplant recipients. The pharmacokinetic (PK) properties of F-ara-A (9-beta-D-arabinosyl-2-fluoradenine) before and after application of busulfan were prospectively investigated in 16 patients with hematological malignancies. The conditioning regimen consisted of intravenous fludarabine 30 mg/m(2) over 30 min from day -6 to day -3, and oral busulfan given at 1 mg/kg every 6 h from day -5 to day -2. PK parameters of F-ara-A, derived from plasma and urine on day -6, -5, -4 and -3, were determined using high-performance liquid chromatography (HPLC). AUC, C(max), t(1/2), Cl(total) and V(SS) were 21.9 microMh, 3.5 microM, 13.0 h, 4.3 l/h/m(2), 60.0 l/m(2) on day -6 and 22.4 microMh, 3.5 microM, 14.0 h, 4.7 l/h/m(2), 69.0 l/m(2) on day -5 to (-2), respectively. Cl(renal) and the urine-recovery were 4.8 l/h, 43.7% of the fludarabine dose on day -6 and 3.9 l/h, 44.2% of the fludarabine dose on day -5 to (-2), respectively. There were no changes in PK parameters of fludarabine given before and after intake of busulfan. This implies that a clinically relevant busulfan-fludarabine drug interaction is unlikely.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Interações Medicamentosas , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/farmacocinéticaRESUMO
An isocratic and sensitive HPLC assay was developed allowing the determination of the new anticancer drug nilotinib (AMN107) in human plasma, urine, culture medium and cell samples. After protein precipitation with perchloric acid, AMN107 underwent an online enrichment using a Zirchrom-PBD precolumn, was separated on a Macherey-Nagel C18-HD column and finally quantified by UV-detection at 258 nm. The total run time is 25 min. The assay demonstrates linearity within a concentration range of 0.005-5.0 microg/ml in plasma (r(2)=0.9998) and 0.1-10.0 microg/ml in urine (r(2)=0.9913). The intra-day precision expressed as coefficients of variation ranged depending on the spiked concentration between 1.27-9.23% in plasma and 1.77-3.29% in urine, respectively. The coefficients of variation of inter-day precision was lower than 10%. Limit of detection was 0.002 microg/ml in plasma and 0.01 microg/ml in urine. The described method is stable, simple, economic and is routinely used for in vivo and in vitro pharmacokinetic studies of AMN107.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/análise , Meios de Cultura , Proteínas de Fusão bcr-abl , Humanos , Pirimidinas/sangue , Pirimidinas/urina , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria UltravioletaRESUMO
High dose busulfan is widely used in preparative regimens for bone marrow transplantation. We describe three cases of accidental busulfan overdosing. Two adults received a single dose of 8 and 18 mg/kg busulfan, respectively. Doses of 9 x 4 mg/kg were ingested by a 14-year-old girl, who experienced seizures. In all cases, no severe liver toxicity including veno-occlusive disease was observed. Plasma samples were obtained from two patients. Busulfan plasma concentrations were far above published values after high-dose busulfan treatment. Busulfan was eliminated by a first-order process. All patients survived these high doses of busulfan and successful transplantation was possible. Two patients died from refractory GvHD on days 91 and 80 after transplantation. One patient is alive in remission after an observation time of 18 months. These cases show that busulfan overdosing may occur and pharmacokinetic evaluation is warranted to estimate risk of early and late toxicity.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Bussulfano/intoxicação , Erros Médicos/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Bussulfano/sangue , Bussulfano/farmacocinética , Overdose de Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Convulsões/induzido quimicamente , Resultado do TratamentoRESUMO
In spite of its broad clinical application in the treatment of malignant disorders, the pharmacokinetics of mitoxantrone are still not fully understood and warrant further investigation. Information is also limited about interindividual differences in the plasma AUC infinity (area-under-the-curve concentration to time infinity) and renal elimination of mitoxantrone and its main metabolites, mono- and dicarboxylic acid. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m2 in 18 patients undergoing combination therapy with mitoxantrone and high-dose cytosine arabinoside for acute myeloid leukemia. Plasma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases with chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m2 mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed for plasma and urine pharmacokinetics. Plasma AUC infinity for mitoxantrone differed approximately 13-fold between individual patients and varied between 80-1030 ngh/ml. The corresponding values for mono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml, respectively. The median terminal half-life for mitoxantrone was similar to that of the mono- and dicarboxylic acid and was 75 h. Cumulative renal elimination ranged from 670-1950 micrograms for mitoxantrone, from 366-852 micrograms for monocarboxylic acid, and from 792-3420 micrograms for dicarboxylic acid. Renal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabolites were 57 and 67 ml/min. In contrast to the great interindividual differences in pharmacokinetic results, a low intraindividual variability was observed upon repeated determinations of renal elimination of mitoxantrone and its metabolites at weekly intervals in five patients. These data provide new insights into the pharmacokinetic of mitoxantrone and its main metabolites revealing substantial differences in drug metabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicity and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.
Assuntos
Mitoxantrona/farmacocinética , Doença Aguda , Adulto , Ácidos Carboxílicos/farmacocinética , Meia-Vida , Humanos , Rim/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Mieloide/metabolismo , Pessoa de Meia-Idade , Mitoxantrona/sangue , Mitoxantrona/urinaRESUMO
The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism of cytosine arabinoside (Ara-C) was comparatively analyzed in normal bone marrow mononuclear cells (NBMMC) from eight healthy volunteers and in leukemic blasts from 50 patients with acute myeloid leukemia (AML). Pretreatment with GM-CSF (100 U/ml) for 48 h resulted in a significant enhancement of DNA synthesis in both cell types: 21 of 35 AML specimens were found to be responsive to GM-CSF as defined by an increase of 3H-TdR incorporation into the DNA > 1.5-fold while NBMMC from normal donors were responsive in all cases. In GM-CSF responsive AML blasts, overall DNA polymerase and DNA polymerase alpha activity increased from a median of 84.4 to 96.1 and from 3.45 to 5.2 pmol/min x mg as compared to a median of 96.7 to 189.9 and 1.2 to 2.2 pmol/min x mg in NBMMC (P < 0.05). Median Ara-C-mediated inhibition of DNA synthesis was significantly more effective in AML blasts as compared to NBMMC (76.5 vs 55.0% at 0.05 microM and 99.0 vs 96.0% at 5.0 microM Ara-C, P < 0.01) but was not influenced by GM-CSF pretreatment. Similarly, intracellular Ara-CTP levels were higher in AML blasts as compared to NBMMC (median of 46.9 vs 18.7 at 1 microM, 167.8 vs 48.0 at 10 microM and 337.5 vs 59.5 ng/10(7) cells at 100 microM extracellular Ara-C, P < 0.01) but showed no enhancement in the presence of GM-CSF. Median deoxycytidine (DCK) and thymidine kinase (TK) activity were only slightly increased in AML blasts after GM-CSF priming. In contrast, NBMMC revealed a significant increase in TK activity after GM-CSF pretreatment (from a median of 1.9 to 3.6 pmol/min x mg, P = 0.039). At low; intermediate and high extracellular Ara-C concentrations GM-CSF pretreatment resulted in a significant enhancement of the 3H-Ara-C incorporation into the DNA in both GM-CSF responsive AML blasts and NBMMC (median of 1.3 to 2.1- and 1.4 to 1.6-fold, P < 0.05). GM-CSF non-responsive AML blasts showed no change in 3H-Ara-C incorporation into the DNA in response to GM-CSF at low Ara-C concentrations but significant increases at intermediate and high extracellular Ara-C concentrations (median increases of 1.63-fold at 1.06 microM with P = 0.01 and 1.37-fold at 10 microM extracellular Ara-C with P = 0.0+005). NBMMC revealed significantly lower GM-CSF-induced increases of the 3H-Ara-C incorporation into the DNA as compared to the effect of GM-CSF priming on DNA synthesis (median increases of 1.4 to 1.7-fold vs 2.6-fold, P < 0.05). These data reveal a different effect of GM-CSF priming on the metabolism of Ara-C in normal vs leukemic cells which may cause a preferential increase in the antileukemic cytotoxicity of Ara-C in the presence of GM-CSF.
Assuntos
Antimetabólitos Antineoplásicos/metabolismo , Medula Óssea/efeitos dos fármacos , Citarabina/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Leucemia Mieloide/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , DNA de Neoplasias/biossíntese , DNA Polimerase Dirigida por DNA/metabolismo , Desoxicitidina Quinase/metabolismo , Interações Medicamentosas , Humanos , Pessoa de Meia-Idade , Timidina Quinase/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Arabinonucleotídeos/farmacocinética , Arabinonucleotídeos/toxicidade , Monofosfato de Citidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Administração Oral , Arabinofuranosiluracila/urina , Arabinonucleotídeos/administração & dosagem , Citarabina/urina , Monofosfato de Citidina/administração & dosagem , Monofosfato de Citidina/farmacocinética , Monofosfato de Citidina/toxicidade , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Estatísticas não ParamétricasRESUMO
The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Células da Medula Óssea , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Citarabina/metabolismo , DNA Polimerase II/metabolismo , DNA de Neoplasias/biossíntese , Daunorrubicina/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda/patologia , Tioguanina/administração & dosagemRESUMO
We report that high-dose 1-beta-D-arabinofuranosylcytosine (Ara-C) treatment leads to substantial changes of membrane lipid composition in human leukemic cell lines. HL 60 cells are at least 10- to 20-fold more sensitive to Ara-C than Raji cells. After 4 h incubation with 50 microM Ara-C, both cells show deviations in their phosphatidylcholine (PC) and triglyceride (TG) contents, starting as early as 8 h after treatment. After 24 h, the Ara-C-induced changes in lipid metabolism are accompanied by a severe loss of viability in HL 60 cells but not in Raji cells. At this time point the HL 60 cells show a 20% depletion of PC with a concomitant increase in TG of 25%, whereas in Raji cells both PC and TG are increased 20 and 22%, respectively. The addition of lysophosphatidylcholine (lysoPC) antagonizes Ara-C-induced cell death in various leukemic cell lines and primary AML blasts from patients. Since lysoPC is a direct precursor for PC and increases the PC content of the membrane, we assume that the loss of PC in the sensitive cell line HL 60 and in other cells plays a role in Ara-C-induced toxicity. Further evidence for this mechanism is presented by the observation that hexadecylphosphocholine, an inhibitor of PC synthesis shows synergistic antiproliferative effects with Ara-C. We conclude that the rapid cell lysis described during high-dose Ara-C treatment seems to be mediated by reduction of cell membrane PC content.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , Fosfatidilcolinas/metabolismo , Arabinofuranosilcitosina Trifosfato/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citarabina/farmacocinética , Células HL-60 , Humanos , Lisofosfatidilcolinas/farmacologiaRESUMO
The current study investigated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine (araC) in leukemic cells of 45 patients with acute myeloid leukemia (AML). AML blasts from bone marrow (BM) (n = 39) and peripheral blood (PB) (n = 17) were incubated for 48 h with or without GM-CSF (100 U/ml) followed by a concurrent treatment with increasing concentrations of araC (0.06-100 microM) for an additional 24 h. After GM-CSF a 1.5-8.4-fold (median 2.3) increase in 3H-araC incorporation into the DNA was observed in ten of 14 peripheral blast specimens and in 23 of 28 bone marrow samples, 18 of whom also showed an enhanced 3H-TdR incorporation (1.5-8.5-fold, median 2.0-fold). Four different types of response were identified when analyzing 3H-araC incorporation into the DNA of bone marrow samples in relation to the applied araC dose: (i) 8/28 cases had increases of the araC incorporation at all araC dose levels applied (0.06-100 microM), (ii) 12/28 at low araC concentrations only (0.06-1.0 microM), (iii) 3/28 at high araC concentrations only (10-100 microM), and (iv) 5/28 showed no increase at any dose level given. Hence, 20 of the 23 responding patients revealed a GM-CSF induced enhancement of araC incorporation at low or conventional doses of araC (0.06-1.0 microM). Fourteen of the 18 cases with concomitant rises of 3H-TdR and 3H-araC incorporation into the DNA after GM-CSF had elevated DNA polymerase alpha activity (16-531%, median 72%) and in ten cases overall DNA polymerase activity was enhanced (10-70%, median 22.5%). In contrast, thymidine kinase (TK) and deoxycytidine kinase (dCK) activity were elevated after GM-CSF in only ten and five patients, respectively. An increase in the fraction of cells in S phase was found in 11/21 bone marrow specimens and in 5/9 peripheral blast samples. However, no correlation was observed between increases in the proportion of cells in S phase and enhancements in enzyme activities. In 13 cases the cytotoxicity of araC with and without GM-CSF was assessed by means of a blast cell colony assay. Preincubation with GM-CSF increased the araC mediated cytotoxicity in ten of 13 patients by a median of 3.2-fold (range 2.2-229-fold). The respective LD50 values for araC were reduced from 0.45 to 0.19 microM on average.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Citarabina/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Leucemia Mieloide Aguda/metabolismo , Adolescente , Adulto , Idoso , Arabinofuranosilcitosina Trifosfato/metabolismo , Citarabina/farmacologia , DNA Polimerase II/metabolismo , DNA de Neoplasias/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Desoxicitidina Quinase/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Fase S , Timidina Quinase/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologiaRESUMO
The increasing insights into the pharmacokinetics and the metabolism of cytosine arabinoside (AraC) have improved the rationale for its application in leukemia therapy and have led to a pharmacologically directed design of antileukemic treatment. The current study aims at adding to this approach by detecting differences in the intracellular metabolism of AraC 5'-triphosphate (AraCTP) between leukemic and normal mononuclear blood cells. Measurements of intracellular AraCTP levels were complemented by determinations of plasma AraC and AraU concentrations and were performed in 32 patients with acute myeloid leukemia undergoing combination therapy including either conventional (100 mg/m2 daily) or high-dose (1.0 or 3.0 g/m2 twice daily) AraC. Plasma AraC concentration showed a linear relationship to the applied AraC dose but did not correlate with intracellular AraCTP levels. During conventional-dose AraC therapy little interpatient variation was observed in AraCTP retention times in leukemic blasts from 5 patients with t1/2 values ranging from 1.70 to 2.50 h (median 2.14 h). In all cases AraCTP levels declined rapidly after the end of the AraC infusion. Substantial differences in AraCTP retention times were revealed, however, during 3 h infusions of either 1.0 or 3.0 g/m2 AraC in leukemic blasts from 10 patients with t1/2 values between 1.60 to 7.63 h (median 2.42 h). In addition, AraCTP levels declined in only one patient by > 10% within the first hour after the end of therapy and remained constant or even increased up to 1.5-fold in a post-treatment period of 1 to 2.5 h in the other nine cases. In contrast, AraCTP retention times were relatively uniform in normal mononuclear blood cells from 11 patients with t1/2 values of 3.34 to 5.29 h (median 3.85 h). More importantly, AraCTP levels dropped by > 10% within the first hour after the end of the high-dose AraC infusion in eight of 11 cases. A post-therapeutic increase > 10% was not observed in any patient. Similar findings emerged after in vitro exposure of normal bone marrow cells from six healthy volunteers to 20 mumol/l AraC for 3 h revealing a > 10% decrease of intracellular AraCTP within the first post-treatment hour in all cases with AraCTP retention times of 2.29 to 8.63 h (median 3.20 h). These differences in AraCTP pharmacokinetics between leukemic and normal blood cells may provide the basis for a modified timing of AraC administration with the aim of selectively maintaining cytotoxic AraCTP levels in leukemic blasts while allowing an intermittent drop of AraCTP levels in normal cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Arabinofuranosilcitosina Trifosfato/metabolismo , Citarabina/farmacocinética , Leucemia Mieloide/sangue , Leucócitos Mononucleares/metabolismo , Doença Aguda , Arabinofuranosilcitosina Trifosfato/análise , Arabinofuranosiluracila/sangue , Arabinofuranosiluracila/farmacocinética , Citarabina/administração & dosagem , Citarabina/sangue , Daunorrubicina/administração & dosagem , Esquema de Medicação , Humanos , Leucemia Mieloide/tratamento farmacológico , Linfoma não Hodgkin/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Tioguanina/administração & dosagemRESUMO
Cytosine arabinoside (ara-C) is one of the most active compounds in the treatment of acute leukemias. In the majority of current protocols ara-C is combined with other cytotoxic agents in an attempt to increase antileukemic activity. The present study investigated the impact of etoposide, teniposide, amsacrine, mitoxantrone, anthracyclines, and asparaginase on the cellular accumulation of ara-C and its intracellular metabolism in order to provide a better rationale for combination therapy. Intracellular accumulation and phosphorylation of ara-C were determined in peripheral blast cells from twenty patients with acute leukemias after exposure to 1 and 10 mumol/l ara-C alone and after preincubation with 1 and 10 micrograms/ml etoposide, 10 and 100 micrograms/ml teniposide, 10 mumol/l amsacrine, 500 ng/ml mitoxantrone (or daunorubicin or doxorubicin) or 10 mumol/l asparaginase. Ara-C accumulation at 10 mumol/l was decreased by 1 microgram/ml etoposide (67 +/- 18% of control), 10 micrograms/ml etoposide (30 +/- 22%), 10 micrograms/ml teniposide (12 +/- 23%), 100 micrograms/ml teniposide (10 +/- 18%), and amsacrine (51 +/- 21%). Intracellular ara-CTP formation was determined at an extracellular concentration of 10 mumol/l and preincubation with these drugs. The intracellular formation of ara-CTP was decreased by 1 microgram/ml etoposide (77 +/- 15% of control), 10 micrograms/ml etoposide (32 +/- 22%), 10 micrograms/ml teniposide (10 +/- 9%), 100 micrograms/ml teniposide (0 +/- 0%), but not by amsacrine. These data indicate that prior exposure to etoposide and teniposide influence ara-C metabolism and possibly cytotoxicity, and thus should not immediately precede ara-C administration in clinical trials.
Assuntos
Arabinofuranosilcitosina Trifosfato/metabolismo , Citarabina/farmacocinética , Etoposídeo/farmacologia , Leucemia/metabolismo , Teniposídeo/farmacologia , Doença Aguda , Adulto , Idoso , Amsacrina/farmacologia , Citarabina/metabolismo , Interações Medicamentosas , Humanos , Leucemia/patologia , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologiaRESUMO
Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicinol in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24 h trough levels show a high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r = 0.78, indicating that the interindividual variation of idarubicin AUC reflects differences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impact of interindividual variations in AUC on clinical outcome and toxicity.
Assuntos
Antibióticos Antineoplásicos/farmacocinética , Idarubicina/farmacocinética , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Administração Oral , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão , Daunorrubicina/análogos & derivados , Daunorrubicina/sangue , Meia-Vida , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/sangue , Linfoma não Hodgkin/sangue , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Análise de RegressãoRESUMO
Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.) -- and cannot be applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 -- a lipophilic prodrug of AraC -- that is resistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase I/II study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m2 (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m2 dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic psi and subsequent beta-oxydation of YNK01 the released AraC (and its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve (ng x h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1 (0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m2 plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m2) while at doses of YNK01 of 450-600 mg/m2 concentrations of standard-dose AraC (100 mg/m2) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.
Assuntos
Antineoplásicos/uso terapêutico , Arabinonucleotídeos/uso terapêutico , Monofosfato de Citidina/análogos & derivados , Leucemia Mieloide/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Doença Aguda , Administração Oral , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Arabinonucleotídeos/efeitos adversos , Arabinonucleotídeos/farmacocinética , Disponibilidade Biológica , Citarabina/farmacocinética , Monofosfato de Citidina/efeitos adversos , Monofosfato de Citidina/farmacocinética , Monofosfato de Citidina/uso terapêutico , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Infusões Intravenosas , Leucemia Mieloide/sangue , Linfoma não Hodgkin/sangue , Taxa de Depuração Metabólica , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Análise de RegressãoRESUMO
Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/metabolismo , Pirimidinas/metabolismo , Rodaminas/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas , Divisão Celular/efeitos dos fármacos , Ciclosporina/farmacologia , Resistência a Múltiplos Medicamentos , Inibidores Enzimáticos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/fisiologia , Regulação Leucêmica da Expressão Gênica , Humanos , Mesilato de Imatinib , Imunossupressores/farmacologia , Células K562/efeitos dos fármacos , Células K562/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Nucleares/metabolismo , Piperazinas/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy at an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under the curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicin in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24-h trough levels shows high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4 - 445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two-fold from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r=0.78, indicating that the interindividual variations of idarubicin AUC reflects differences in absorptions rather than metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24-h trough level shows such an excellent correlation (r=0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24-h trough level may allow the assessment of the impact of interindividual variations in AUC of clinical outcome and toxicity.
Assuntos
Antibióticos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idarubicina/farmacocinética , Leucemia Mieloide/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Doença Aguda , Administração Oral , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Cromatografia Líquida de Alta Pressão , Citarabina/administração & dosagem , Daunorrubicina/análogos & derivados , Daunorrubicina/sangue , Esquema de Medicação , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide/sangue , Linfoma não Hodgkin/sangue , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/farmacocinética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/urina , Área Sob a Curva , Simulação por Computador , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Modelos Biológicos , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/sangue , Compostos Organoplatínicos/urina , OxaliplatinaRESUMO
The present randomized trial addressed the pending question whether cytosine arabinoside (AraC) should be given at high or intermediate dose to patients with relapsed or refractory acute myeloid leukemia. Based upon the previously established regimen of the sequential administration of AraC and mitoxantrone (S-HAM) patients below 60 years of age were randomized to receive AraC at either 3.0 g/m2 vs. 1.0 g/m2 per dose while older patients were randomly assigned to either 1.0 g/m2 or 0.5 g/m2 AraC. Concurrent pharmacokinetic analyses were performed to determine the plasma AraC pharmacokinetics as well as the intracellular AraCTP peak concentrations and retention times. At the present stage 65 patients are evaluable for response and toxicity. Complete remissions were achieved at similar frequencies for patients treated with 3.0 g/m2 or 1.0 g/m2 AraC with 56% and 50%, respectively. Reasons for failure were different, however, with a higher incidence of resistant disease in patients treated with 1.0 g/m2 AraC and more early deaths in the higher dose treatment group. Pharmacokinetic studies indicated a homogeneous distribution of AraC plasma concentrations but a substantial interpatient variability for intracellular AraCTP peak concentrations and retention times.