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BACKGROUND/AIM: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). MATERIALS AND METHODS: microRNA expression changes induced by hypoxia in human GEC cell lines were measured with microarrays and validated by quantitative real-time polymerase chain reaction. Candidate HRMs were measured in pre-therapeutic tumor samples from 195 patients with GEC. RESULTS: Expression of miR-210 was shown to be significantly induced in esophageal squamous cell carcinoma (9.26-fold, p<0.001) and adenocarcinoma cell lines (4.95-fold, p<0.001) and miR-27a-star was significantly up-regulated in adenocarcinoma cell lines (4.79-fold, p=0.04). A weak but significant correlation between miR-210 expression and a 15-gene hypoxia signature was observed (Pearson r correlation: r=0.38, p<0.001). No significant associations of HRMs and clinical outcome in patients with GEC were identified. CONCLUSION: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM.
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Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , MicroARNs/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Hipoxia de la Célula , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS). Approximately 80% of NF2 patients also have intracranial meningiomas. Vascular endothelial growth factor (VEGF) is expressed in both NF2-related and sporadic occurring meningiomas and anti-VEGF therapy (bevacizumab) may, therefore, be beneficial in NF2-related meningiomas. The purpose of the study was to report the effect of bevacizumab on meningiomas in NF2 patients. MATERIALS AND METHODS: We retrospectively reviewed the effect of bevacizumab on the cross-sectional area (CSA) of 14 intracranial meningiomas in 7 NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every two weeks for six months and 15 mg/kg every three weeks thereafter. Patients were evaluated according to the modified Macdonald criteria with repeated magnetic resonance (MR) scans. RESULTS: The median duration of therapy was 27 months (range 16-34) and 42 MR scans (median 8, range 4-11) were reviewed. The median annual change in meningioma CSA prior to bevacizumab was 2% (range -4%-+76%). During treatment, a decrease in meningioma CSA was observed in 5 of 14 meningiomas (36%) in 5 of 7 patients (71%). The median decrease in CSA was -10% (range -3%--25%). One meningioma (7%) progressed and the remaining (93%) had stable disease. CONCLUSIONS: Bevacizumab may slow or reverse the growth of some NF-related meningiomas. However, we have previously reported a fatal case of intracerebral hemorrhage following bevacizumab in NF2 patients, wherefore, this effect needs to be balanced carefully against the risk of side effects.
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Inhibidores de la Angiogénesis/farmacología , Bevacizumab/farmacología , Neoplasias Meníngeas/tratamiento farmacológico , Meningioma/tratamiento farmacológico , Neurofibromatosis 2/complicaciones , Evaluación de Resultado en la Atención de Salud , Adulto , Inhibidores de la Angiogénesis/administración & dosificación , Bevacizumab/administración & dosificación , Femenino , Humanos , Masculino , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/etiología , Meningioma/diagnóstico por imagen , Meningioma/etiología , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544-0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375-0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578-0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556-1.191) or sunitinib (HR: 0.997; 95% CI: 0.782-1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).
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Carcinoma de Células Renales/tratamiento farmacológico , Aprobación de Drogas , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Axitinib , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Europa (Continente) , Humanos , Indoles/administración & dosificación , Pirroles/administración & dosificación , Sunitinib , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS) and severe hearing loss is common in NF2 patients. Vascular endothelial growth factor (VEGF) expression level in NF2 correlates with tumour growth rate and bevacizumab, a VEGF-binding antibody, has previously been shown to induce tumour shrinkage and improve hearing. We retrospectively reviewed the effect of bevacizumab on hearing and VS tumour size in 12 consecutive NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every second week for 6 months; hereafter, bevacizumab 15 mg/kg was administered every third week. Patients were evaluated with repeated audiometries, MR scans and clinical evaluations. Radiological response was defined as a 20 % or greater reduction in VS volume. A total of 398 treatments (median 36) were administered and the median duration on therapy was 22 months (range 7-34). We observed a radiological response (≥20 % tumour shrinkage) in seven out of 18 tumours (39 %) in six out of 12 patients (50 %). Sustained radiological responses were maintained in six tumours (33 %) for more than 2 months. Three patients had objectively improved hearing and five patients reported subjective benefit in neurological symptoms, including improved hearing. Toxicity was in general manageable; however, one patient died from cerebral haemorrhage which was possibly related to therapy. In conclusion, bevacizumab improved hearing and reduced the size of VS in some patients with progressive NF2 which corroborates previous findings; however, the risk of severe side effects should be carefully considered and discussed with the patients prior to treatment.
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Bevacizumab , Hemorragia Cerebral/etiología , Audición/efectos de los fármacos , Neurofibromatosis 2 , Neuroma Acústico , Carga Tumoral/efectos de los fármacos , Adulto , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Audiometría/métodos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neurofibromatosis 2/tratamiento farmacológico , Neurofibromatosis 2/metabolismo , Neurofibromatosis 2/patología , Neuroma Acústico/tratamiento farmacológico , Neuroma Acústico/metabolismo , Neuroma Acústico/patología , Estudios Retrospectivos , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM. MATERIAL AND METHODS: After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity. RESULTS: The response rate was 32% (95% CI 17-51%) for Bev-Tem (n = 32) and 23% (95% CI 9-44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable. CONCLUSIONS: Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.
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Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Quimioradioterapia/métodos , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Neoplasias Encefálicas/mortalidad , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Quimioradioterapia/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Temozolomida , Resultado del TratamientoRESUMEN
The European Commission issued on March 17, 2011, a marketing authorization valid throughout the European Union (EU) for eribulin (Halaven; Eisai Limited). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a marketing authorization for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least 2 chemotherapeutic regimens for advanced disease. Eribulin mesylate is a structurally simplified synthetic analogue of halichondrin B, which is a natural product isolated from the marine sponge Halichondria okadai (ATC code L01XX41). Eribulin is a nontaxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into nonproductive aggregates leading to G(2)-M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage. The recommended dose of eribulin is 1.23 mg/m(2) (equivalent to 1.4 mg/m(2) eribulin mesylate) to be administered intravenously over 2 to 5 min on days 1 and 8 of a 3-week cycle. In the pivotal trial, eribulin was associated with increased overall survival in patients with locally advanced or metastatic breast cancer who received at least 2 prior chemotherapy lines for advanced disease (median overall survival was 13.2 months in the eribulin arm vs. 10.6 months in the control arm; HR = 0.805; 95% confidence interval, 0.677-0.958; P = 0.014). The most common side effects are asthenia or fatigue and neutropenia. The objective of this article is to summarize the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary report and product information, including product characteristics, are available on the European Medicines Agency website.
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Antineoplásicos , Neoplasias de la Mama/tratamiento farmacológico , Furanos , Cetonas , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Neoplasias de la Mama/patología , Ensayos Clínicos Fase III como Asunto , Europa (Continente) , Femenino , Furanos/administración & dosificación , Furanos/efectos adversos , Furanos/química , Furanos/farmacocinética , Agencias de los Sistemas de Salud , Humanos , Estimación de Kaplan-Meier , Cetonas/administración & dosificación , Cetonas/efectos adversos , Cetonas/química , Cetonas/farmacocinética , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Resultado del TratamientoRESUMEN
The bisdioxopiperazines such as (+)-(S)-4,4'-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), and 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione (ICRF-193) are agents that inhibit eukaryotic topoisomerase II, whereas their ring-opened hydrolysis products are strong iron chelator. The clinically approved analog ICRF-187 is a pharmacological modulator of topoisomerase II poisons such as etoposide in preclinical animal models. ICRF-187 is also used to protect against anthracycline-induced cardiomyopathy and has recently been approved as an antidote for alleviating tissue damage and necrosis after accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question of whether their pharmacological in vivo effects are mediated through interaction with topoisomerase II or via their intracellular iron chelating activity. In an attempt to distinguish between these possibilities, we here present a transgenic mouse model aimed at identifying the contribution of topoisomerase IIalpha to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIalpha, demonstrated previously to render the human ortholog of this enzyme highly resistant toward bisdioxopiperazines, was introduced at the TOP2A locus in mouse embryonic stem cells by targeted homologous recombination. These cells were used for the generation of transgenic TOP2A(Y165S/+) mice, which were demonstrated to be resistant toward the general toxicity of both ICRF-187 and ICRF-193. Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2A(Y165S/+) mice, highlighting the role of topoisomerase IIalpha in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed.
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Antígenos de Neoplasias/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , Proteínas de Unión al ADN/efectos de los fármacos , Piperazinas/farmacología , Razoxano/farmacología , Animales , Antígenos de Neoplasias/metabolismo , Secuencia de Bases , Western Blotting , Cartilla de ADN , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Dicetopiperazinas , Femenino , Ratones , Ratones Transgénicos , Mutagénesis Sitio-Dirigida , Proteínas de Unión a Poli-ADP-RibosaRESUMEN
In a number of cancer types high tumor tissue levels of plasminogen activator inhibitor type 1 (PAI-1) protein are strongly associated with shorter cancer patient survival. This association has been intriguing since PAI-1 is known to inhibit urokinase plasminogen activator (uPA) that converts plasminogen to plasmin, which is actively involved in tumor progression and invasion. In order to further explore the biological role of PAI-1 in cancer, we have prepared fibroblasts from PAI-1 gene deficient mice and from their wild type littermates. From these fibroblasts fibrosarcoma cell lines were established and characterized. Both types of fibroblasts underwent spontaneous transformation as indicated by aneuploidy, immortalization, clonogenicity in soft agar and tumor formation in vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation rates in vitro, cells devoid of PAI-1 were significantly more sensitive to apoptotic stimuli. When inoculated subcutaneously into nude mice PAI-1 expressing cells rapidly established tumors, while PAI-1 deficient cells had a significantly longer lag-phase before they started to grow (p<0.0001). The present study suggests that PAI-1, besides its uPA inhibiting function, has a role in cancer progression by protecting tumor cells from undergoing apoptosis.
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Apoptosis/fisiología , Fibrosarcoma/fisiopatología , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Neoplasias de los Tejidos Blandos/fisiopatología , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Femenino , Fibroblastos/citología , Fibrosarcoma/patología , Masculino , Ratones , Ratones Mutantes , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy. EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX). RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks. CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/radioterapia , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/efectos de la radiación , Neoplasias del Sistema Nervioso Central/patología , Terapia Combinada , Daño del ADN , ADN de Neoplasias/efectos de los fármacos , ADN de Neoplasias/genética , ADN de Neoplasias/efectos de la radiación , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Etopósido/administración & dosificación , Femenino , Ratones , Ratones Endogámicos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/radioterapia , Razoxano/administración & dosificación , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Plasminogen activator inhibitor-1 (PAI-1) inhibits the activation of the plasminogen activator system, the latter being involved in cancer growth and dissemination. Interestingly, PAI-1 is elevated in many solid tumours and this elevation has consistently been shown to be associated with shorter length of patient survival. This study aims to determine whether PAI-1 contributes to cancer cell growth by inhibiting apoptosis of tumour cells. It is shown that spontaneous transformation decreases cellular sensitivity to chemotherapy-mediated apoptosis of wild-type, but not PAI-1 gene-deficient, fibrosarcomas. PAI-1 gene-deficient and wild-type mice displayed similar sensitivity to treatment with etoposide, suggesting a differential effect of PAI-1 expression between cancer cells and normal cells. Thus, since PAI-1 appears to be an important factor in regulating apoptosis in cancer cells but not in normal cells, inhibitors of PAI-1 might be useful as sensitising pre-treatment for subsequent apoptosis-inducing anti-cancer therapy.
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Apoptosis/fisiología , Fibroblastos/patología , Fibrosarcoma/patología , Neoplasias Pulmonares/patología , Inhibidor 1 de Activador Plasminogénico/genética , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Transformación Celular Neoplásica , Relación Dosis-Respuesta a Droga , Etopósido/farmacología , Fibrosarcoma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Ratones , Inhibidor 1 de Activador Plasminogénico/deficienciaRESUMEN
PURPOSE: The anthracyclines daunorubicin and doxorubicin and the epipodophyllotoxin etoposide are potent DNA cleavage-enhancing drugs that are widely used in clinical oncology; however, myelosuppression and cardiac toxicity limit their use. Dexrazoxane (ICRF-187) is recommended for protection against anthracycline-induced cardiotoxicity. EXPERIMENTAL DESIGN: Because of their widespread use, the hematologic toxicity following coadministration of dexrazoxane and these three structurally different DNA cleavage enhancers was investigated: Sensitivity of human and murine blood progenitor cells to etoposide, daunorubicin, and doxorubicin +/- dexrazoxane was determined in granulocyte-macrophage colony forming assays. Likewise, in vivo, B6D2F1 mice were treated with etoposide, daunorubicin, and doxorubicin, with or without dexrazoxane over a wide range of doses: posttreatment, a full hematologic evaluation was done. RESULTS: Nontoxic doses of dexrazoxane reduced myelosuppression and weight loss from daunorubicin and etoposide in mice and antagonized their antiproliferative effects in the colony assay; however, dexrazoxane neither reduced myelosuppression, weight loss, nor the in vitro cytotoxicity from doxorubicin. CONCLUSION: Although our findings support the observation that dexrazoxane reduces neither hematologic activity nor antitumor activity from doxorubicin clinically, the potent antagonism of daunorubicin activity raises concern; a possible interference with anticancer efficacy certainly would call for renewed attention. Our data also suggest that significant etoposide dose escalation is perhaps possible by the use of dexrazoxane. Clinical trials in patients with brain metastases combining dexrazoxane and high doses of etoposide is ongoing with the aim of improving efficacy without aggravating hematologic toxicity. If successful, this represents an exciting mechanism for pharmacologic regulation of side effects from cytotoxic chemotherapy.
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Anemia/prevención & control , Antibióticos Antineoplásicos/efectos adversos , Antineoplásicos/efectos adversos , Fármacos Cardiovasculares/farmacología , Daunorrubicina/efectos adversos , Doxorrubicina/efectos adversos , Etopósido/efectos adversos , Leucopenia/prevención & control , Neutropenia/prevención & control , Razoxano/farmacología , Trombocitopenia/prevención & control , Anemia/inducido químicamente , Animales , Técnicas de Cultivo de Célula , Ensayo de Unidades Formadoras de Colonias , Femenino , Leucopenia/inducido químicamente , Ratones , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
PURPOSE: The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide. METHODS: Etoposide plasma levels were determined by HPLC. RESULTS: The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses. CONCLUSIONS: The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.
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Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/secundario , Carcinoma de Células Pequeñas/sangre , Carcinoma de Células Pequeñas/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Área Bajo la Curva , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Catéteres de Permanencia , Cromatografía Líquida de Alta Presión , Etopósido/administración & dosificación , Etopósido/sangre , Humanos , Infusiones Intravenosas , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Razoxano/administración & dosificación , Razoxano/sangreRESUMEN
PURPOSE: The study was undertaken to determine the metabolism of dexrazoxane (ICRF-187) to its one-ring open hydrolysis products and its two-rings opened metal-chelating product ADR-925 in cancer patients with brain metastases treated with high-dose etoposide. In this phase I/II trial dexrazoxane was used as a rescue agent to reduce the extracerebral toxicity of etoposide. METHODS: Dexrazoxane and its one-ring open hydrolysis products were determined by HPLC and ADR-925 was determined by a fluorescence flow injection assay. RESULTS: The two one-ring open hydrolysis intermediates of dexrazoxane appeared in the plasma at low levels upon completion of dexrazoxane infusion and then rapidly decreased with half-lives of 0.6 and 2.5 h. A plasma concentration of 10 micro M ADR-925 was also detected at the completion of the dexrazoxane i.v. infusion period, indicating that dexrazoxane was rapidly metabolized in vivo. A plateau level of 30 micro M ADR-925 was maintained for 4 h and then slowly decreased. The pharmacokinetics of dexrazoxane were found to be similar to other reported data in other settings and at lower doses. CONCLUSIONS: The rapid appearance of ADR-925 in plasma may make ADR-925 available to be taken up by heart tissue and bind free iron. These results suggest that the dexrazoxane intermediates are enzymatically metabolized to ADR-925 and provide a pharmacodynamic basis for the antioxidant cardioprotective activity of dexrazoxane.