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Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/genética , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Neoplasias Cerebelosas/patología , Niño , Preescolar , Proteínas de Unión al ADN/genética , Femenino , Humanos , Masculino , Meduloblastoma/patología , Mutación , Proteínas de Neoplasias/genéticaRESUMEN
BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.
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Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab , Progresión de la Enfermedad , Esquema de Medicación , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors.
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Carcinoma de Células Escamosas/patología , Receptores ErbB/fisiología , Neoplasias de Cabeza y Cuello/patología , Invasividad Neoplásica , Factor de Transcripción STAT3/metabolismo , Carcinoma de Células Escamosas/genética , Receptores ErbB/genética , Neoplasias de Cabeza y Cuello/genética , HumanosRESUMEN
BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Bevacizumab , Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/mortalidad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Glioma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia del Tratamiento , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteins MutLalpha or MutSalpha indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.
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Antineoplásicos Alquilantes/farmacología , Carmustina/farmacología , Proteínas de Ciclo Celular/fisiología , Reparación de la Incompatibilidad de ADN/fisiología , Proteínas Quinasas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/antagonistas & inhibidores , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Daño del ADN/fisiología , Enzimas Reparadoras del ADN/genética , Activación Enzimática , Humanos , Proteínas MutL , Proteína MutS de Unión a los Apareamientos Incorrectos del ADN/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Subunidades de Proteína/genética , Fase S , Transducción de SeñalRESUMEN
The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.
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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Cerebelosas/genética , Ciclofosfamida/análogos & derivados , Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Meduloblastoma/genética , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2 , Transportadoras de Casetes de Unión a ATP/genética , Aldehído Deshidrogenasa , Familia de Aldehído Deshidrogenasa 1 , Aldehído Deshidrogenasa Mitocondrial , Aldehído Oxidorreductasas/genética , Aldehído Reductasa/genética , Aldo-Ceto Reductasas , Línea Celular Tumoral , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/enzimología , Ciclofosfamida/uso terapéutico , Interpretación Estadística de Datos , Perfilación de la Expresión Génica/métodos , Regulación Enzimológica de la Expresión Génica , Genotipo , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/enzimología , Análisis de Secuencia por Matrices de Oligonucleótidos , FenotipoRESUMEN
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.
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Neoplasias Encefálicas/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Glioma/metabolismo , Invasividad Neoplásica , Osteonectina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular , Glioma/patología , Humanos , ARN Interferente PequeñoRESUMEN
PURPOSE: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts. METHODS: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)]. RESULTS: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001). CONCLUSION: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carbazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glioma/tratamiento farmacológico , Glucósidos/uso terapéutico , Indoles , Inhibidores de Topoisomerasa I , Adulto , Animales , Niño , Femenino , Humanos , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Tasa de Supervivencia , Trasplante Heterólogo , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Receptor-mediated internalization of monoclonal antibodies (mAbs), such as those specific for the epidermal growth factor receptor variant III (EGFRvIII), can lead to rapid loss of radioactivity from the target cell. In the current study, the anti-EGFRvIII mAb L8A4 was radioiodinated using two methods -N-succinimidyl 5-iodo-3-pyridinecarboxylate (SIPC) and via a D-amino acid peptide LysArgTyrArgArg (D-KRYRR). Paired-label internalization assays performed on EGFRvIII-expressing U87DeltaEGFR cells in vitro demonstrated that labeling L8A4 using D-KRYRR resulted in significantly higher retention of radioiodine in the intracellular compartment. In athymic mice with D256 human glioma xenografts, tumor uptake was similar for both labeling methods through 24 hr. However, an up to fourfold higher tumor retention was observed for mAb labeled with the D-amino acid peptide at later time points. Radiation absorbed dose calculations based on these biodistribution data indicated that L8A4 labeled using D-KRYRR exhibited better tumor-to-normal-organ radiation dose ratios, suggesting that this labeling method may be of particular value for labeling internalizing mAbs.
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Anticuerpos Monoclonales/química , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacología , Oligopéptidos/síntesis química , Radiofármacos/síntesis química , Succinimidas/síntesis química , Succinimidas/farmacología , Animales , Anticuerpos Monoclonales/farmacocinética , Glioma/patología , Humanos , Radioisótopos de Yodo , Marcaje Isotópico , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Oligopéptidos/farmacocinética , Radiometría , Radiofármacos/farmacocinética , Distribución Tisular , Células Tumorales CultivadasRESUMEN
PURPOSE: Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice. METHODS: Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR)) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals. RESULTS: Karenitecin produced statistically significant (P < or = 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90+ days in D-212 MG and D-341 MED. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). CONCLUSION: These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors.
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Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Femenino , Humanos , Irinotecán , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Trasplante HeterólogoAsunto(s)
Receptores ErbB/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/inmunología , Glioblastoma/terapia , Humanos , Inmunotoxinas/inmunología , Inmunotoxinas/uso terapéutico , MutaciónRESUMEN
Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.
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Anticuerpos Monoclonales/uso terapéutico , Radioisótopos de Yodo/uso terapéutico , Melanoma/radioterapia , Meningitis/etiología , Radiofármacos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Sulfatos de Condroitina/inmunología , Femenino , Humanos , Radioisótopos de Yodo/efectos adversos , Selectina L/inmunología , Persona de Mediana Edad , Radiofármacos/efectos adversosRESUMEN
Gliomas remain one of the deadliest forms of cancer. Improved therapeutics will require a better understanding of the molecular nature of these tumors. We, therefore, mimicked the most common genetic changes found in grade III-IV gliomas, disruption of the p53 and RB pathways and activation of telomere maintenance and independence from growth factors, through the ectopic expression of the SV40 T/t-Ag oncogene, an oncogenic form of H-ras (H-ras(V12G)), and the human telomerase catalytic subunit hTERT in normal human astrocytes. The resulting cells displayed many of the hallmarks of grade III-IV gliomas, including greatly expanded life span and growth in soft agar and, most importantly, were tumorigenic with pathology consistent with grade III-IV neuroectodermal tumors in mice. This model system will, for the first time, allow the biological significance of selected genetic alterations to be studied in human gliomas.
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Transformación Celular Viral/genética , Glioma/genética , ARN , Animales , Antígenos Transformadores de Poliomavirus/biosíntesis , Antígenos Transformadores de Poliomavirus/genética , Astrocitos/metabolismo , Astrocitos/patología , Astrocitos/fisiología , Dominio Catalítico , Proteínas de Unión al ADN , Genes ras , Glioma/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratones SCID , Retroviridae/genética , Telomerasa/biosíntesis , Telomerasa/genética , Células Tumorales CultivadasRESUMEN
PURPOSE: This study was conducted to define the activity of irofulven in the treatment of a series of xenografts derived from human glioblastoma multiforme growing subcutaneously and intracranially in athymic nude mice. METHODS: Athymic mice bearing subcutaneous or intracranial tumors were treated with irofulven at a 10% lethal dose with responses compared to tumor-bearing mice treated with drug vehicle. RESULTS: Irofulven was active against all tumor lines tested with growth delays ranging from 5.6 to 81.6 days (all values statistically significant, P < or = 0.001). Irofulven also produced a statistically significant (P < or = 0.001) increase in the median survival of mice bearing D-456 intracranial xenografts with a 162% increase in median survival. CONCLUSIONS: Irofulven is active in a spectrum of human glioblastoma multiforme-derived xenografts and evaluation in patients with this neoplasm is warranted.
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Antineoplásicos Alquilantes/uso terapéutico , Glioblastoma/tratamiento farmacológico , Sesquiterpenos/uso terapéutico , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante HeterólogoRESUMEN
Combinatorial variation of CDR3 of V(H) and V(L), followed by phage display, was used to select affinity mutants of the parental anti-epidermal growth factor receptor-vIII (EGFRvIII) scFv MR1. One mutant, MR1-1(scFv), had increased specific binding affinity for EGFRvIII. It was produced and radiolabeled, and its biodistribution was evaluated in human glioma-bearing athymic mice. MR1-1 targeted the same EGFRvIII epitope as MR1 with an approximately 15-fold higher affinity (K(d) = 1.5 x 10(-9) M) measured by surface resonance analysis. Labeling with (131)I or (125)I was performed, and the immunoreactive fraction of the labeled MR1-1(scFv) was 50% to 55%. After incubation at 37 degrees C for 4 days, the binding affinity was maintained at 60% of initial levels. The specificity of MR1-1 for EGFRvIII was demonstrated in vitro by flow cytometry and incubation of FITC-labeled scFv with the EGFRvIII-expressing U87MG. DeltaEGFR cell line or with the EGFRvIII-negative U87MG cell line in the presence or absence of competing unlabeled MR1-1(scFv). We also investigated the internalization and processing of MR1-1 compared with MR1; MR1-1 exhibited levels of both cell surface retention and internalization up to 5 times higher than those by MR1. In biodistribution studies performed in athymic mice bearing s.c. U87MG. DeltaEGFR tumor xenografts, animals received paired-label intratumoral infusions of (131)I-labeled MR1-1(scFv) and (125)I-labeled MR1(scFv). Our results showed an up to 244% +/- 77% increase in tumor uptake for MR1-1 compared with that for MR1. The improved tumor retention of MR1-1(scFv) combined with its rapid clearance from normal tissues also resulted in sustained higher tumor:normal organ ratios. These results suggest that the improved affinity of MR1-1 can significantly impact in vivo glioma-specific targeting and immunotherapy.
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Afinidad de Anticuerpos , Receptores ErbB/metabolismo , Glioma/metabolismo , Región Variable de Inmunoglobulina/metabolismo , Inmunotoxinas/metabolismo , Secuencia de Aminoácidos , Animales , Membrana Celular/metabolismo , Receptores ErbB/inmunología , Femenino , Glioma/inmunología , Región Variable de Inmunoglobulina/inmunología , Inmunotoxinas/inmunología , Inmunotoxinas/farmacocinética , Radioisótopos de Yodo/metabolismo , Radioisótopos de Yodo/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Distribución Tisular , Trasplante HeterólogoRESUMEN
PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.
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Anticuerpos Monoclonales/uso terapéutico , Glioma/radioterapia , Inmunotoxinas/uso terapéutico , Neoplasias Supratentoriales/radioterapia , Tenascina/inmunología , Adulto , Anciano , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Terapia Combinada , Femenino , Estudios de Seguimiento , Glioma/diagnóstico por imagen , Glioma/cirugía , Humanos , Inmunotoxinas/efectos adversos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Supratentoriales/diagnóstico por imagen , Neoplasias Supratentoriales/cirugía , Análisis de Supervivencia , Tomografía Computarizada de EmisiónRESUMEN
PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Astrocitoma/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Guanina/análogos & derivados , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Astrocitoma/sangre , Carmustina/administración & dosificación , Carmustina/efectos adversos , Carmustina/farmacocinética , Neoplasias del Sistema Nervioso Central/sangre , Esquema de Medicación , Glioblastoma/sangre , Guanina/administración & dosificación , Guanina/efectos adversos , Guanina/sangre , Guanina/farmacocinética , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Catéteres de Permanencia , Dacarbazina/análogos & derivados , Dacarbazina/administración & dosificación , Sistemas de Liberación de Medicamentos , Glioma/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/uso terapéutico , Encéfalo/efectos de los fármacos , Cateterismo , Dacarbazina/uso terapéutico , Humanos , Masculino , Trasplante de Neoplasias , Ratas , Ratas Desnudas , Temozolomida , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Temozolomide, an imidazole tetrazinone, and CPT-11, a camptothecin derivative, have previously been shown to have anti-central nervous system tumor activity in laboratory and clinical studies. The current experiments were designed to evaluate the activity of temozolomide plus CPT-11 against a malignant glioma-derived xenograft, D-54 MG, growing s.c. in athymic nude mice. The initial schedule of i.p. drug administration was temozolomide at 0.1 LD10 on day 1 and CPT-11 at 0.1 LD10 on days 1-5 and 8-14. The combination of these two agents produced greater than additive activity against D-54 MG. This enhanced activity was maintained when the initial administration of CPT-11 was delayed to day 3 or day 5. However, when CPT-11 was administered first on day 1 using 0.5 LD10 (for the single dose schedule) followed by temozolomide (0.1 LD10) 5 h, 3 days, or 5 days later, the enhancement of activity was substantially reduced. These results demonstrate that the combination of temozolomide plus CPT-11 displays a schedule-dependent enhancement of antitumor activity, suggest a mechanistic explanation for the enhanced activity, and provide the rationale for a Phase I trial of this regimen.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Dacarbazina/análogos & derivados , Dacarbazina/administración & dosificación , Dacarbazina/uso terapéutico , Neoplasias del Sistema Nervioso/tratamiento farmacológico , Animales , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Femenino , Humanos , Irinotecán , Masculino , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Temozolomida , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Genes expressed specifically in malignant tissue may have potential as therapeutic targets but have been difficult to locate for most cancers. The information hidden within certain public databases can reveal RNA transcripts specifically expressed in transformed tissue. To be useful, database information must be verified and a more complete pattern of tissue expression must be demonstrated. We tested database mining plus rapid screening by fluorescent-PCR expression comparison (F-PEC) as an approach to locate candidate brain tumor antigens. Cancer Genome Anatomy Project (CGAP) data was mined for genes highly expressed in glioblastoma multiforme. From 13 mined genes, seven showed potential as possible tumor markers or antigens as determined by further expression profiling. Now that large-scale expression information is readily available for many of the commonly occurring cancers, other candidate tumor markers or antigens could be located and evaluated with this approach.