RESUMO
BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.
Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias/tratamento farmacológico , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Amplificação de Genes , Humanos , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Medicina de Precisão/métodos , Intervalo Livre de Progressão , Receptor ErbB-2/antagonistas & inibidores , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC. PATIENTS AND METHODS: Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS). RESULTS: In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%). CONCLUSIONS: Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Fluoruracila/administração & dosagem , Genótipo , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Irinotecano , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras) , Receptores de IgG/genética , Resultado do TratamentoRESUMO
The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.
RESUMO
Extremely sweet proteins isolated from tropical fruit extracts are promising healthy alternatives to sugar and synthetic sweeteners. Sweetness and taste in general are, however, still poorly understood. The engineering of stable sweet proteins with tailored properties is made difficult by the lack of supporting high-resolution structural data. Experimental information on charge distribution, protonation states and solvent structure are vital for an understanding of the mechanism through which sweet proteins interact with taste receptors. Neutron studies of the crystal structures of sweet proteins allow a detailed study of these biophysical properties, as illustrated by a neutron study on the native protein thaumatin in which deuterium labelling was used to improve data quality.
Assuntos
Deutério/química , Proteínas de Plantas/química , Edulcorantes/química , Modelos Moleculares , Conformação ProteicaRESUMO
Seed extracts from Moringa oleifera are of wide interest for use in water purification where they can play an important role in flocculation; they also have potential as anti-microbial agents. Previous work has focused on the crude protein extract. Here we describe the detailed biophysical characterization of individual proteins from these seeds. The results provide new insights relating to the active compounds involved. One fraction, designated Mo-CBP3, has been characterized at a molecular level using a range of biochemical and biophysical techniques including liquid chromatography, X-ray diffraction, mass spectrometry, and neutron reflection. The interfacial behavior is of particular interest in considering water purification applications and interactions with both charged (e.g. silica) and uncharged (alumina) surfaces were studied. The reflection studies show that, in marked contrast to the crude extract, only a single layer of the purified Mo-CBP3 binds to a silica interface and that there is no binding to an alumina interface. These observations are consistent with the crystallographic structure of Mo-CBP3-4, which is one of the main isoforms of the Mo-CBP3 fraction. The results are put in context of previous studies of the properties of the crude extract. This work shows possible routes to development of separation processes that would be based on the specific properties of individual proteins.
Assuntos
Moringa oleifera/química , Proteínas de Plantas/química , Sementes/química , Purificação da Água , Adsorção , Óxido de Alumínio/química , Óxido de Alumínio/isolamento & purificação , Sequência de Aminoácidos , Floculação , Modelos Moleculares , Conformação Proteica , Dióxido de Silício/química , Dióxido de Silício/isolamento & purificação , Purificação da Água/métodosRESUMO
The crystal structure of recombinant Dps2 (DRB0092, DNA protecting protein under starved conditions) from the Gram-positive, radiation-resistant bacterium Deinococcus radiodurans has been determined in its apo and iron loaded states. Like other members of the Dps family, the bacterial DrDps2 assembles as a spherical dodecamer with an outer shell diameter of 90 A and an interior diameter of 40 A. A total of five iron sites were located in the iron loaded structure, representing the first stages of iron biomineralisation. Each subunit contains a mononuclear iron ferroxidase centre coordinated by residues highly conserved amongst the Dps family of proteins. In the structures presented, a distinct iron site is observed 6.1 A from the ferroxidase centre with a unique ligand configuration of mono coordination by the protein and no bridging ligand to the ferroxidase centre. A non-specific metallic binding site, suspected to play a regulative role in iron uptake/release from the cage, was found in a pocket located near to the external edge of the C-terminal 3-fold channel.
Assuntos
Proteínas de Bactérias/química , Deinococcus/química , Ferro/metabolismo , Porinas/química , Sequência de Aminoácidos , Apoproteínas/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Ceruloplasmina/química , Cristalografia por Raios X , Dimerização , Modelos Moleculares , Dados de Sequência Molecular , Dobramento de Proteína , Estrutura Secundária de Proteína , Alinhamento de Sequência , Eletricidade EstáticaRESUMO
We describe a novel self-assembling supramolecular nanotube system formed by a heterocyclic cationic molecule which was originally designed for its potential as an antiparasitic and DNA sequence recognition agent. Our structural characterisation work indicates that the nanotubes form via a hierarchical assembly mechanism that can be triggered and tuned by well-defined concentrations of simple alkali halide salts in water. The nanotubes assembled in NaCl have inner and outer diameters of ca. 22 nm and 26 nm respectively, with lengths that reach into several microns. Our results suggest the tubes consist of DB921 molecules stacked along the direction of the nanotube long axis. The tubes are stabilised by face-to-face π-π stacking and ionic interactions between the charged amidinium groups of the ligand and the negative halide ions. The assembly process of the nanotubes was followed using small-angle X-ray and neutron scattering, transmission electron microscopy and ultraviolet/visible spectroscopy. Our data demonstrate that assembly occurs through the formation of intermediate ribbon-like structures that in turn form helices that tighten and compact to form the final stable filament. This assembly process was tested using different alkali-metal salts, showing a strong preference for chloride or bromide anions and with little dependency on the type of cation. Our data further demonstrates the existence of a critical anion concentration above which the rate of self-assembly is greatly enhanced.
Assuntos
Álcalis , Amidinas/química , Benzimidazóis/química , DNA/química , Halogênios/química , Nanotubos/química , LigantesRESUMO
The cloning, expression, purification, crystallization and preliminary crystallographic analysis of glucose-1-phosphate uridylyltransferase (UgpG) from Sphingomonas elodea ATCC 31461 bound to glucose-1-phosphate are reported. Diffraction data sets were obtained from seven crystal forms in five different space groups, with highest resolutions ranging from 4.20 to 2.65 A. The phase problem was solved for a P2(1) crystal form using multiple isomorphous replacement with anomalous scattering from an osmium derivative and a SeMet derivative. The best native crystal in space group P2(1) has unit-cell parameters a = 105.5, b = 85.7, c = 151.8 A, beta = 105.2 degrees . Model building and refinement are currently under way.
Assuntos
Proteínas de Bactérias/química , Glucofosfatos/metabolismo , Sphingomonas/enzimologia , Sphingomonas/genética , UTP-Glucose-1-Fosfato Uridililtransferase/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação/genética , Clonagem Molecular , Cristalização , Cristalografia por Raios X/métodos , Regulação Bacteriana da Expressão Gênica , Glucofosfatos/química , Glucofosfatos/genética , Especificidade por Substrato/genética , UTP-Glucose-1-Fosfato Uridililtransferase/biossíntese , UTP-Glucose-1-Fosfato Uridililtransferase/genéticaRESUMO
Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.
Assuntos
Cardiomiopatias/patologia , Coração/efeitos dos fármacos , Adulto , Idoso , Biópsia , Cardiomiopatias/induzido quimicamente , Doxorrubicina , Endocárdio/efeitos dos fármacos , Endocárdio/ultraestrutura , Epirubicina , Feminino , Coração/efeitos da radiação , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Miocárdio/ultraestruturaRESUMO
Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERα and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERα-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERα+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERα-positive breast cancers.
Assuntos
Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/metabolismo , Queratina-5/metabolismo , Aldosterona/farmacologia , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Dexametasona/farmacologia , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Humanos , Receptores de Hialuronatos/biossíntese , Células MCF-7 , Camundongos , Camundongos Nus , Mineralocorticoides/farmacologia , Recidiva Local de Neoplasia/genética , Transplante de Neoplasias , Progestinas/farmacologia , Prognóstico , Prolactina/farmacologia , Proteínas Proto-Oncogênicas c-bcl-6 , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Progesterona/genética , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Transplante Heterólogo , Regulação para CimaRESUMO
PURPOSE: Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay. PATIENTS AND METHODS: Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter. RESULTS: Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P <.05) at doses >/= 2.5 mg/kg. CONCLUSION: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Tionucleotídeos/farmacocinética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Proteínas Proto-Oncogênicas c-raf/genética , RNA Mensageiro/metabolismo , Tionucleotídeos/efeitos adversosRESUMO
Longer follow up and greater numbers of patients will be required to determine the ultimate curative potential of surgery sparing regimens. Current reports suggest that combination chemotherapy and radiotherapy is equivalent to abdominoperineal resection. Furthermore, the incidence of local recurrence in most series suggests that abdominoperineal resection alone may be insufficient for locoregional control of disease. Patients with canal tumors who develop recurrent disease to inguinal nodes should be treated by groin dissection. Local recurrence of tumors at the anal margin can be satisfactorily treated by further local excision or by groin dissection if there are inguinal node metastases. Further studies are needed to evaluate the efficacy of chemotherapy and irradiation in pelvic recurrence following abdominoperineal resection. Further clinical trials to develop more effective salvage therapy in visceral metastatic disease are needed.
Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Dosagem RadioterapêuticaRESUMO
Carcinoembryonic antigen (CEA) was first described more than three decades ago, when its presence was demonstrated in fetal gut tissue and in tumors from the gastrointestinal tract. Subsequently, CEA was detected in the circulation of patients and recognized as a serum marker for colorectal cancer. In the early diagnosis of disease recurrence following surgical resection, a serial increase in CEA level is the first evidence of tumor. In patients with disseminated tumors, serial determinations are useful for monitoring response to therapy. Carcinoembryonic antigen values decrease with effective treatment, while they increase with disease refractory to therapy or progressive metastases, yet the utility of CEA in the management of patients with advanced colorectal cancer remains controversial.
Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Anticorpos Monoclonais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Humanos , Imunoterapia , Programas de Rastreamento , Período Pós-Operatório , Prognóstico , RadioimunodetecçãoRESUMO
Although monoclonal antibodies offer great promise for treating patients with malignant disease, much research is needed in the future. The potential uses include antibody directed diagnosis and therapy in GI carcinomas. Through innovative strategies directed toward the application of chemistry of these biological agents, developments in the understanding of the mechanisms of oncogenesis and molecular biology, more sophisticated clinical applications of antibody directed therapies will change the scope of cancer therapy in the future.
Assuntos
Anticorpos Monoclonais/imunologia , Biomarcadores Tumorais/imunologia , Neoplasias Gastrointestinais/imunologia , Antígenos de Neoplasias/imunologia , Antígenos Glicosídicos Associados a Tumores , Antígeno Carcinoembrionário/imunologia , Epitopos/imunologia , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Humanos , Imuno-Histoquímica , ImunoterapiaRESUMO
Patients with untreated extensive small cell lung cancer (SCLC) with CALGB performance scores 0-2 were treated with etoposide 200 mg/m2/day on days 1-3 and cisplatin doses of 20, 30, or 35 mg/m2/day days 1-3 in a Phase I/II format. Of the nine patients treated at the 35 mg/m2/day cisplatin dose in the Phase I portion of the study, Grade 4 leukopenia occurred in five patients and Grade 4 thrombocytopenia in four. There were two deaths due to myelosuppression and sepsis. This dose was thus considered the maximum tolerated dose (MTD), and a Phase II trial was then conducted using this treatment program. In the Phase II trial of 39 patients, the objective response rate was 67% (95% confidence interval, 50-81%) with 21% complete responses (CI 9-36%). Median survival was 10.5 months. Grade 4-5 leukopenia was seen in 57% and Grade 4-5 thrombocytopenia in 56%. The MTD defined by this Phase I trial represents a 67-100% increase in etoposide and a 32-42% increase in cisplatin dosage compared to prior studies. The observed objective response rates with this regimen are comparable to studies using conventional doses, but hematological toxicity was higher.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Irinotecan (CPT-11, Camptosar) is a semisynthetic water-soluble derivative of the plant alkaloid camptothecin. This review will focus on the potential use of irinotecan in combination with fluorouracil (5-FU) in the preoperative combined-modality treatment of advanced rectal cancer. The laboratory studies that define the mechanism of fluoropyrimidine- and camptothecin-mediated radiosensitization are discussed, and the rationale for combined-modality therapy using radiation with 5-FU and irinotecan is presented.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Retais/tratamento farmacológico , Camptotecina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Doses de Radiação , Neoplasias Retais/radioterapia , Resultado do TratamentoRESUMO
No adequate second- or third-line therapy is available in the United States for patients with metastatic colorectal cancer and disease progression following treatment with fluorouracil (5-FU)-based therapy and an irinotecan (CPT-11, Camptosar)-containing regimen, or a combination of the two. Oxaliplatin (Eloxatin), a new platinum analog, has demonstrated high activity in the treatment of colorectal cancer, especially when combined with 5-FU and leucovorin. The combination of oxaliplatin and 5-FU/leucovorin has been approved in Europe for the first- and second-line treatment of colorectal cancer. This compassionate-use study was initiated because of the unavailability of the agent in the United States and inadequate US safety data. The following review summarizes data from this ongoing study, the primary focus of which is to provide oxaliplatin for compassionate use until it receives US Food and Drug Administration approval and becomes available commercially.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/secundário , Relação Dose-Resposta a Droga , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Resultado do TratamentoRESUMO
Colorectal cancer is the second leading cause of cancer-related deaths in men and women in the United States. In 1997, it is estimated that 131,200 new cases of colorectal cancer will be diagnosed and 54,900 deaths will occur due to the disease. Although the tumor is localized at the time of diagnosis and resection with curative intent is possible in approximately 75% of patients, more than a third will develop disease recurrence. Consequently, almost half of all patients with colorectal cancer will die of metastatic disease.