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1.
Cytopathology ; 27(2): 103-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25757141

RESUMO

OBJECTIVE: As the diagnosis of non-small cell lung cancer (NSCLC) is based on cytology in around 70% of cases, it is important to use the same material for molecular analyses. Fluorescence in situ hybridization (FISH) is the only approved test for the detection of the translocation and inversion of anaplastic lymphoma kinase (ALK), but the optimal procedures for the fixation or staining of the sample before FISH evaluation have not been established. We investigated whether ALK gene status determined by FISH in a prospectively enrolled case series of patients was affected by fixation and staining. METHODS: One hundred and fifteen cytological samples were obtained by transbronchial needle aspiration (TBNA) or endobronchial ultrasound (EBUS)-TBNA from 109 patients with NSCLC. All samples were evaluated for epidermal growth factor receptor (EGFR) mutation by pyrosequencing and for ALK rearrangement by FISH. Specimens for ALK determination had been fixed with Cytofix(®) and/or Carnoy's solution or 10% formalin (cell blocks) and variously stained. RESULTS: Sixteen (14%) of the 115 samples were mutated for EGFR and 99 (86%) showed wild-type EGFR status. Of these 115 samples, 79 (69%) were negative for echinoderm microtubule-associated protein like 4 (EML4)-ALK translocation, nine (8%) were positive and 27 (23%) were unevaluable. In particular, 19 (26%) of the 72 Papanicolaou-stained smears fixed with Cytofix were unevaluable because of inadequate samples or cell overlapping; neither of the two May-Grünwald-Giemsa-stained samples were evaluable. Ten of 17 smears used for rapid on-site evaluation (ROSE) and immediately post-fixed in Carnoy's solution or 80% alcohol were evaluable. CONCLUSIONS: In this series, smears were unevaluable as a result of inadequate samples, cell overlapping or lack of fixation performed immediately after FNA.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Receptores ErbB/genética , Proteínas de Fusão Oncogênica/isolamento & purificação , Receptores Proteína Tirosina Quinases/isolamento & purificação , Idoso , Quinase do Linfoma Anaplásico , Biópsia por Agulha/métodos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Translocação Genética/genética
2.
Cytopathology ; 26(5): 297-302, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25123949

RESUMO

BACKGROUND: Although fine needle aspiration (FNA) is the standard diagnostic test for the characterization of a suspicious thyroid nodule, in some cases cytological evaluation is inconclusive. The aim of this study was to determine the role of BRAF mutation in aiding diagnosis and to verify whether archival cytological samples could be suitable for molecular analysis. METHODS: Eighty-five patients with suspicious (Thy4) or follicular (Thy3) lesions on cytology were resubmitted to a second FNA for BRAF mutation analysis. Of these, 56 subsequently underwent surgery. The usefulness of archival samples for molecular analysis was also studied in a second cohort of 42 patients with a confirmed diagnosis of papillary thyroid carcinoma for whom both archived paraffin-embedded histological samples and cytological smears were available. A further 15 patients with paired fresh FNA and archived cytological and histological samples were recruited. RESULTS: BRAF mutation was found in the fresh FNA samples from 10 of 56 patients who had surgery with previous inconclusive cytology (4/45, 9%, Thy3 and 6/11, 55%, Thy4). The BRAF test showed a specificity and positive predictive value of 100% (26/26 and 10/10, respectively), sensitivity of 33% (10/30) and negative predictive value of 57% (26/46). There was absolute concordance between the BRAF results obtained with 42 histological and cytological archived samples. BRAF analysis on 15 archived cytological samples showed absolute concordance with histology, whereas there was one false negative on the matched fresh FNA. CONCLUSION: BRAF analysis is a highly specific test that can facilitate cytological diagnosis in some cases and can also be performed on archived cytological samples.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Carcinoma Papilar , Citodiagnóstico/métodos , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Mutação/genética , Sensibilidade e Especificidade , Câncer Papilífero da Tireoide
3.
Ann Oncol ; 22(10): 2294-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21339385

RESUMO

BACKGROUND: There is a need to improve the performance of urine cytology in bladder cancer diagnosis. We assessed the diagnostic performance of (i) telomerase activity detected by telomeric repeat amplification protocol (TRAP) assay, (ii) cytology and TRAP assay in parallel, (iii) cytology in parallel with the in-series combination of TRAP assay and FISH analysis, and (iv) the in-series combination of TRAP assay and FISH analysis. PATIENTS AND METHODS: Cross-sectional study of 289 consecutive patients who presented with urinary symptoms at a north Italian hospital between 2007 and 2008. All underwent cystoscopy and cytology evaluation, and conclusive results were available for TRAP assay and FISH analysis. RESULTS: Sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the combination of cytology and TRAP; 0.78 and 0.78 for the combination of cytology, TRAP, and FISH; and 0.65 and 0.93 for the combination of TRAP and FISH. All differences versus cytology alone were significant (P ≤ 0.011). CONCLUSION: Compared with cytology alone, the combination of cytology, TRAP, and FISH provided the best trade-off between increase in sensitivity and loss in specificity, especially among non-bleeding patients, low-grade cancers, and early-stage cancers.


Assuntos
Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Cistoscopia , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico , Sensibilidade e Especificidade , Telomerase/metabolismo , Telômero/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
4.
Tumour Biol ; 29(3): 145-51, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18612219

RESUMO

BACKGROUND: The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients. METHODS: Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients. RESULTS: In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors. CONCLUSION: We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.


Assuntos
Alelos , Arginina/genética , Neoplasias da Mama/genética , Códon/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Supressora de Tumor p53/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Hipóxia/fisiopatologia , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Prolina/genética , Transfecção , Regulação para Cima
5.
Anticancer Res ; 28(1A): 315-20, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18383863

RESUMO

Studies on cyclopentenone prostaglandins (CPPGs), clavulones and other cyclopentenones have shown that these compounds have a significant anticancer activity mediated by their cyclopentenone (CP) chemical moiety. In this study the cytotoxicity against cancer cells of the model compound cyclopent-2-en-1-one (2CP) was investigated. Being a highly water soluble small molecule, 2CP could be an ideal candidate to overcome pharmacological issues related to drug delivery and penetration. Its cytotoxic activity was tested on various melanoma and lung cancer cells. Interestingly, 2CP was both cytotoxic and pro-apoptotic, more pronounced on melanoma cells, at concentrations in the sub-micromolar range. On melanoma cells its mechanism of action was mediated by the mitochondria and the activation of caspase 3.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ciclopentanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Melanoma/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos
6.
Oncology ; 72(1-2): 118-24, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18004083

RESUMO

OBJECTIVE: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. METHODS: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT. RESULTS: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity). CONCLUSIONS: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Esquema de Medicação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Leucovorina/administração & dosagem , Dose Máxima Tolerável , Pessoa de Meia-Idade , Modelos Teóricos , Metástase Neoplásica , Paclitaxel/administração & dosagem , Tegafur/administração & dosagem , Uracila/administração & dosagem
7.
J Exp Ther Oncol ; 6(1): 23-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17228521

RESUMO

Cell membrane ion transporters expression and activity are altered in cancer cells and these phenotypic alterations offer potential targets for cancer therapies. Among the therapeutic agents affecting cell membrane transporters, serotonin reuptake inhibitors (SSRIs) have been shown to have anticancer potential. In this work, we have compared two SSRIs, one very specific for serotonin reuptake transporters (paroxetine) and another which also inhibit norepinephrine and dopamine transporters (venlafaxine), for their ability to counteract growth of various murine and human cancer cell lines. We found that paroxetine has cytotoxic activity against tumor cells, both of murine or human origin in the micromolar concentration range, whereas venlafaxine has not. A neurotransmitter receptor mediated mechanism of action appears thus unlikely for SSRIs cytotoxicity on cancer cells. With ranges of SSRIs cytotoxicity on cancer cells defined, limits in their possible applicability in cancer therapy is discussed.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Antidepressivos/farmacologia , Benzimidazóis/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Cicloexanóis/farmacologia , Fibroblastos/metabolismo , Humanos , Íons , Camundongos , Necrose/patologia , Paroxetina/farmacologia , Propídio/farmacologia , Cloridrato de Venlafaxina
8.
Cancer Res ; 50(10): 2943-8, 1990 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-2334895

RESUMO

These studies describe the clinical correlations of 63 in vitro chemosensitivity assays on breast cancer cells after short-term monolayer culture. Forty-five of the assays were single agent correlations. Based on cut-off values determined empirically, the test accurately predicted resistance for 36 of 41 patients (88%) who did not respond to the drug. It also predicted sensitivity with a high degree of accuracy: 21 of 22 patients (95%) who responded to the drug tested had a sensitive assay. In five cases, two biopsies were evaluated from the same patient. Whenever assays were performed before and after treatment with a given drug, tumor cells from the second biopsy were more resistant in vitro if the patient failed on therapy. If the patient did not fail, but stopped therapy for other reasons, or if there was no intervening therapy with the tested drug, the two biopsies remained similar in drug sensitivity. These results suggest that in vitro chemosensitivity assays which accurately predict both sensitivity and resistance can be obtained with breast cancer cells after short-term culture and that further prospective trials are warranted.


Assuntos
Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Neoplasias da Mama/patologia , Carcinoma/patologia , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/toxicidade , Daunorrubicina/análogos & derivados , Daunorrubicina/toxicidade , Doxorrubicina/toxicidade , Epirubicina/toxicidade , Humanos , Técnicas In Vitro , Prognóstico , Células Tumorais Cultivadas/efeitos dos fármacos , Vimblastina/toxicidade
9.
Cancer Biol Ther ; 4(10): 1089-95, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16082196

RESUMO

High expression of the epidermal growth factor receptor (EGFR) family confers a growth advantage on malignant cells in various tumor types. Most pancreatic cancers express EGFR, which seems to play an important role in the acquisition of aggressive clinical behaviour and in tumor invasion. Iressa (ZD1839), a quinazoline tyrosine kinase inhibitor selective for the EGF receptor, has shown good anti-tumor activity in both preclinical and clinical studies. Using two pancreatic cancer cell lines that express different EGFR and ErbB-2 levels, we analyzed the activity of Iressa and evaluated its modulation effect on four conventional cytotoxic drugs: gemcitabine, oxaliplatin, docetaxel and SN38. Iressa was tested at scalar doses up to the plasma peak level concentration and showed a similar weak cytostatic effect in both cell lines. Conversely, an additive or weak synergistic effect was observed when the drug was administered simultaneously with or following cytotoxic drugs. Our data show that Iressa has only a weak activity at doses within the plasmatic peak concentration and that its effect is independent of EGFR and p42/p44 expression and phosphorylation levels. This is in agreement with recent literature data that attribute an essential role to a specific EGFR mutation in mediating response to Iressa. This mutation was absent in both pancreatic cell lines tested.


Assuntos
Antineoplásicos/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Quinazolinas/farmacologia , Antineoplásicos/sangue , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Inibidores Enzimáticos/sangue , Receptores ErbB/efeitos dos fármacos , Gefitinibe , Humanos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Quinazolinas/sangue
10.
Clin Cancer Res ; 7(3): 590-3, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11297253

RESUMO

Detection of genetic alterations in exfoliated intestinal cells in stool could represent an alternative, noninvasive tool for the screening of colorectal tumors. To verify this, we analyzed p53 and K-ras mutations and microsatellite instability on 46 cases of colorectal cancer and compared the presence of molecular alterations in tumor tissue and stool samples from individual patients. p53 exons 5-8 and K-ras exons 1-2 were analyzed by denaturing gradient gel electrophoresis. For the microsatellite instability, a set of 5 microsatellite markers (D2S123, D5S346, D17S250, BAT25, and BAT26) was evaluated. In the 18 healthy individuals, no genetic alterations in either tissue or stool were detected. p53 mutations were detected in 17 (37%), K-ras alterations in 15 (33%), and microsatellite instabilities in 5 (11%) of the 46 tumors analyzed. In a side study, we analyzed the correlation in genetic alteration profiles between tumors and macroscopically normal or healthy tissue from the same patient. The presence of at least one molecular alteration in tumor was observed in 31 (67%) of the cases. p53, K-ras mutations, and microsatellite instabilities were detected in stool samples in 18, 40, and 60% of patients with tumors harboring the same alterations. Due to the largely complementary presence of p53 and K-ras mutations in tumors, the use of highly sensitive procedures for stool analysis could offer a means competitive with colonoscopy and the fecal occult blood test.


Assuntos
Análise Mutacional de DNA/métodos , Genes p53/genética , Genes ras/genética , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Eletroforese em Gel de Poliacrilamida , Éxons , Fezes , Humanos , Repetições de Microssatélites
11.
Cell Prolif ; 33(2): 75-89, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10845252

RESUMO

Cell kinetics holds a prominent role among biological factors in predicting clinical outcome and response to treatment in neoplastic patients. Different cell kinetic variables are often considered as valid alternatives to each other, but the limited size of case series analysed in several studies and the lack of simultaneous determinations of all the variables on the same tumours do not justify this conclusion. In the present study, the correlation between [3H]thymidine labelling index ([3H]dT LI), flow cytometric S phase cell fraction (FCM-S) and Ki-67 immunoreactivity (Ki-67/MIB-1) was verified and the type of correlation with the most important clinical, pathological and biological patient and tumour characteristics was investigated in a very large series of breast cancer patients. Ki-67/MIB-1, FCM-S and [3H]dT LI were determined in 609, 526 and 485 patients, respectively, and all three cell proliferation indices were evaluated in parallel on the same tumour in a series of 330 breast cancer patients. All the cell kinetic determinations were performed within the context of National Quality Control Programmes. Very poor correlation coefficients (ranging from 0.37 to 0.18) were observed between the different cell kinetic variables determined in parallel on the same series of breast cancers. Moreover, Ki-67/MIB-1 and FCM-S showed a significant relationship with histological type, grade and tumour size, whereas statistically significant correlations were not observed for [3H]dT LI. In conclusion, the results show that the different cell kinetic variables provide different biological information and cannot be considered as alternatives to each other.


Assuntos
Neoplasias da Mama/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Nucleares , Neoplasias da Mama/química , Ciclo Celular/fisiologia , Proteínas de Ligação a DNA/análise , Feminino , Citometria de Fluxo , Humanos , Antígeno Ki-67/análise , Pessoa de Meia-Idade , Proteínas Nucleares/análise , Pós-Menopausa , Pré-Menopausa , Prognóstico , Estudos Prospectivos , Fase S/fisiologia , Timidina/farmacologia , Trítio
12.
Crit Rev Oncol Hematol ; 37(1): 69-82, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11164721

RESUMO

Today, drug combinations are frequently used in the treatment of cancer to increase therapeutic efficacy. Currently used clinical protocols for cancer combination therapies are mainly obtained empirically or on the basis of results from previous clinical trials. Information obtained from clinical protocols is invaluable, but it is time-consuming, expensive and does not provide data on the biochemical and molecular mechanisms of interaction of the drugs used in combination treatments at cellular level. Therefore, in vitro drug combination studies on established cell lines or primary cell cultures play an important role in designing and optimising combination protocols. A variety of in vitro assays and different mathematics models have been developed to investigate cytotoxic effects and to analyse the type of drug interactions. Increased knowledge of the cellular targets of traditional and new drugs and the development of new technologies have resulted in a new role for the in vitro tests which are no longer used only to evaluate the cytotoxic effects of drugs, but also to investigate the interference on cell cycle, induction of apoptosis and molecular or biochemical interactions. A review on in vitro preclinical tests used to evaluate the effects of drug combinations and to design the rationale of combined chemotherapy protocols is presented.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Técnicas de Cultura de Células , Avaliação Pré-Clínica de Medicamentos/normas , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Modelos Biológicos
13.
Eur J Cancer ; 34(5): 724-30, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9713281

RESUMO

A new human cancer cell line was established from a metastatic lesion of a small cell lung carcinoma (SCLC-R1) and maintained in continuous culture with a doubling time of 62 h. The SCLC-R1 line, whose ultrastructural features are presented, showed a diploid DNA content, a translocation involving chromosome 16 [t(16;?)(q24;?)] and noticeable deletions in the FHIT (fragile histidine triad) region in the short arm of chromosome 3 [del(3)(p14)] and in the telomeric region of the short arm of chromosome 12 [del(12)(p13)]. The involvement of 12p in metastatic small cell lung cancer is reported here for the first time. No amplification or rearrangements were evident in the c-myc, L-myc, N-myc, int-2, c-erbB-2, H-ras, K-ras, c-mos, and hst-1 genes by Southern blot analysis. Wild-type p53, RB, K-ras and H-ras genes were evident by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. The neuron specific enolase (NSE) level was much higher in the cell line's cytosol than in the patient's serum and the cell line also had high expression of chromogranin A and cytokeratin 19. SCLC-R1 cells were sensitive to cisplatin, carboplatin and doxorubicin. The clinical history of the patient from whom the cell line was derived is reported. The characteristics of this new cell line indicate it to be a useful experimental model to investigate lung cancer biology and anticancer drug response.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/genética , Aberrações Cromossômicas , Neoplasias Pulmonares/genética , Células Tumorais Cultivadas/efeitos dos fármacos , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/metabolismo , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Diploide , Deleção de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas Proto-Oncogênicas/metabolismo , Translocação Genética , Células Tumorais Cultivadas/patologia
14.
Semin Oncol ; 24(5 Suppl 17): S17-19-S17-25, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9374087

RESUMO

Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial, 19 patients received bolus doxorubicin (50 mg/m2) followed after a 16-hour interval by paclitaxel (given at dose levels ranging from 130 to 250 mg/m2) by 3-hour infusion every 3 weeks, for a maximum of eight cycles. Paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem
15.
Semin Oncol ; 23(5 Suppl 11): 16-22, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8893894

RESUMO

Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer (either untreated or relapsed after adjuvant therapy). In the phase I study, 19 enrolled patients received bolus doxorubicin (50 mg/m2) and, after a 16-hour interval, escalating doses of paclitaxel (from 130 to 250 mg/m2 in 30-mg/ m2 increments) by 3-hour infusion every 3 weeks for a maximum of eight cycles. Paclitaxel doses were increased if the maximum tolerated dose (MTD; defined by dose-limiting toxicities) had not been reached. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (< 500/microL) in 20% of cycles with no significant clinical events. No relevant clinical cardiotoxicity was observed. Other toxicities included mild peripheral neuropathy and mild myalgia/arthralgia (In 37.5% and 30.4% of cycles, respectively). The maximum tolerated paclitaxel dose was not reached at the 250 mg/m2 dose level. In the second phase, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2, the dose level immediately preceding the highest paclitaxel dose used in phase I). Grade 4 neutropenia occurred in 36 of the 87 cycles but was complicated by fever in only eight cycles (9%); three patients needed granulocyte colony-stimulating factor. Peripheral neuropathy (grades 1 and 2 in 41.3% and 5.7% of cycles, respectively) and a myalgic syndrome (grades 1 and 2 in 24.1% and 17.2% of cycles, respectively) were observed. No significant clinical cardiotoxicity was observed in 12 of the 13 patients. One patient experienced a decrease in left ventricular ejection fraction (from 60% to 43%) at a cumulative doxorubicin dose of 400 mg/m2. Antitumor efficacy was evaluated in both phase I and phase II. Overall clinical responses included 10 complete (31.3%) and 15 partial (46.9%) responses, for an objective response rate of 78.1%. Six patients (18.8%) had stable disease. The median durations of objective and complete response were 9 and 7 months, respectively. The 78.9% objective response rate in the phase I trial (31.6% complete and 47.3% partial responses) suggests a dose response relationship: at paclitaxel dose > or = 190 mg/m2, all patients had an objective response (six complete and nine partial responses). These results confirm that doxorubicin followed by paclitaxel is active and should be tested as adjuvant treatment and in patients treated previously with anthracyclines.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Artralgia/induzido quimicamente , Quimioterapia Adjuvante , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Coração/efeitos dos fármacos , Humanos , Infusões Intravenosas , Injeções Intravenosas , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Neutropenia/induzido quimicamente , Paclitaxel/efeitos adversos , Dor/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Indução de Remissão , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
16.
Semin Oncol ; 23(5 Suppl 12): 22-8, 1996 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8941407

RESUMO

In phase I and II studies we administered fixed doses of doxorubicin by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for the treatment of patients with advanced breast cancer who had received no prior treatment or who had relapsed after adjuvant therapy. Nineteen patients were entered in the study from April 1994 to February 1995. The median age of participants was 54 years; the median disease-free interval was 328 days. Eleven patients had undergone prior adjuvant chemotherapy, seven had undergone prior hormonal therapy, and six had undergone chest radiotherapy. A total of 128 courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 to 250 mg/m2, through dose escalations of 30 mg/m2 if maximum tolerated dose was not reached) were repeated every 21 days for a median of seven cycles per patient. Toxicities encountered in this trial included grade 4 neutropenia (20% of courses) and grade 4 thrombocytopenia (3% of courses). No grade 3 or 4 nonhematologic toxicities were observed (World Health Organization grade I peripheral neuropathies and mild myalgias in 37.5% and 30% of courses, respectively). No cardiac toxicity was observed. Responses included six complete responses (31.6%), nine partial responses (47.2%), and three stable disease (15.8%), for an overall response rate of 78.8%. Median duration of overall and complete response was 8+ months and 7+ months, respectively. At dose levels > or = 190 mg/m2, all patients had achieved a response (six complete responses and six partial responses). A phase II trial using fixed doses of doxorubicin (50 mg/m2) and paclitaxel (220 mg/m2) is ongoing. Preliminary data on 71 courses report no cardiac toxicity. Treatment with paclitaxel has been well tolerated at each dose level. The maximum tolerated dose was not reached at 250 mg/m2. No cardiac toxicity was reported. The dosing sequence of doxorubicin followed by paclitaxel is a highly active regimen and needs to be tested in anthracycline patients and in an adjuvant setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Paclitaxel/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Indução de Remissão
17.
Semin Oncol ; 23(1 Suppl 1): 19-23, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8629031

RESUMO

We designed a clinical study in which fixed doses of doxorubicin were infused by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, princeton, NJ) for the treatment of patients with advanced breast cancer, an interval selected to allow systemic clearance of doxorubicin before administration of paclitaxel in an outpatient setting. Courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 mg/m2 to 250 mg/m2 via dose escalation of 30 mg/m2) were repeated every 21 days, to a maximum of eight cycles. Maximum tolerated dose was reached if two or more of six patients at a given dose level were affected by the following events: absolute neutrophil count less than 500/microliter for > or = 7 days, absolute neutrophil count less than 100/microliter for > or = 3 days, insufficient hematopoietic recovery with absolute neutrophil count less than 1,500/microliter on day 21, febrile neutropenia, grade 4 thrombocytopenia, any World Health Organization grade 3 nonhematologic toxicity for more than 7 days. There were 19 patients enrolled; the patients received a total of 128 treatment courses. Grade 4 neutropenia was the main side effect, occurring in 20% of courses but generally not associated with clinical events. No relevant clinical cardiac toxicity or alteration of left ventricular ejection fraction was observed. Other toxicities included complete alopecia, mild peripheral neuropathy, and mild myalgia. There was a reduction of one dose level for moderate myalgia in one patient (190 mg/m2 level). Complete alopecia was always present. Maximum tolerated dose was not reached at paclitaxel 250 mg/m2. Ultimately, the introduction of this combination in the adjuvant setting is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/patologia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos
18.
J Cancer Res Clin Oncol ; 122(4): 237-42, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8601577

RESUMO

We established a novel cancer cell line (MAST) from the ascitic fluid of a metastatic infiltrating ductal carcinoma of the breast. The epithelial and neoplastic nature of the MAST cells was confirmed by ultrastructural analysis. The cell line was maintained as a monolayer with a doubling time of about 68 h, and it possessed an abnormal karyotype with a modal chromosome number of 60, a trisomy of chromosome 18 and other unidentified rearranged chromosomes. Among the markers consistently found in MAST metaphases, we noted a t(14; 14) and a very large subtelocentric, a large satellited acrocentric and a very large submetacentric chromosome with striking fluorescent bands. Immunoenzymatic assay demonstrated that the MAST cell line was positive for estrogen and progesterone receptors. The in vitro drug-sensitivity assay showed a marked resistance of the cell line to 5-fluorouracil and 4-hydroperoxycyclophosphamide and a moderate resistance to etoposide and 4'-epidoxorubicin. The molecular analysis showed a four-to sixfold amplification of the c-myc gene and no amplification or rearrangement of the int-2, c-erbB-2, c-Ha-ras, c-mos and hst-1 genes.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Células Tumorais Cultivadas , Adulto , Ascite , Biomarcadores Tumorais/análise , Divisão Celular , Bandeamento Cromossômico , DNA de Neoplasias/genética , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Genes myc , Humanos , Microscopia Eletrônica
19.
Cancer Genet Cytogenet ; 105(2): 152-9, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9723033

RESUMO

Two gastric cancer cell lines, AKG and GK2, were established from a pleural and an ascitic effusion, respectively. GK2 cells have a pseudodiploid karyotype with an add(6)(q27) chromosome in all metaphases examined. The karyotype of AKG cells is highly rearranged: FISH analysis with painting probes has shown that DNA sequences derived from single chromosomes are scattered on several (as many as eight) markers. In this cell line, the C-MYC and the K-RAS oncogenes are amplified. The organization and the copy number of the C-MYC-amplified units are different from the K-RAS units, suggesting that the two oncogenes were amplified independently. The presence of a few marker chromosomes carrying both C-MYC and K-RAS could be due to translocation events that followed the amplification.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas , Animais , Testes de Carcinogenicidade , Carcinoma/tratamento farmacológico , Divisão Celular , Aberrações Cromossômicas , Resistencia a Medicamentos Antineoplásicos , Feminino , Dosagem de Genes , Rearranjo Gênico , Genes myc , Genes ras , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Gástricas/tratamento farmacológico
20.
Cancer Genet Cytogenet ; 107(1): 11-20, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9809028

RESUMO

Two human cancer cell lines were established from metastatic lesions of an adenocarcinoma (RAL) and a squamous cell (CAEP) carcinoma of the lung. The clinical histories of the patients from whom the cell lines were derived are reported. The lines were maintained in continuous culture with doubling times of 65 (RAL) and 50 (CAEP) hours. The RAL and CAEP cell lines, whose morphology and ultrastructural features are presented, showed extensively rearranged karyotypes with modal number of 85 (RAL) and 98 (CAEP). In particular, chromosome 2 pentasomy and several clonal markers were evident in the RAL cells, whereas a telomeric deletion of chromosome 1, del (1)(q32), was observed in the CAEP cells. The morphologic data were confirmed by high expression of specific antigens for each histotype. A marked positivity of the neuron-specific enolase (NSE) levels was evident by immunoenzymatic assays in the cell lines cytosol with respect to those present in the respective patient's sera. No amplification or rearrangements were evident in the CMYC, LMYC, NMYC, INT-2, ERBB2, HRAS, KRAS, MOS, HST-1 genes by Southern blotting analysis in each cell line. Point mutations in exon 1 of KRAS and in exon 7 of TP53 were evident by polymerase chain reaction (PCR)-DNA sequencing in the RAL cell line, whereas no alterations were present in the HRAS and RB genes. The four genes studied did not show point mutations in the CAEP cell line. The RAL cell line was resistant to all the drugs tested, whereas the CAEP cells were sensitive to vinblastine. These cell lines may represent useful experimental models to investigate lung cancer biology and anticancer drug response.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Células Tumorais Cultivadas , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/metabolismo , Antígeno Carcinoembrionário/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Marcadores Genéticos , Humanos , Cariotipagem , Queratinas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fosfopiruvato Hidratase/metabolismo
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