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1.
Ann Oncol ; 27(4): 648-53, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26802153

RESUMO

BACKGROUND: In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS: Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS: PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ≥2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION: Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV: NCT00844649.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Gencitabina
2.
Ann Oncol ; 27(4): 654-60, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26802160

RESUMO

BACKGROUND: A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS: Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS: Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION: This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/administração & dosagem , Antígeno CA-19-9/sangue , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/sangue , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores Farmacológicos/sangue , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , Gencitabina
3.
J Clin Oncol ; 41(36): 5482-5492, 2023 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-38100992

RESUMO

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

5.
Nat Med ; 3(6): 639-45, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9176490

RESUMO

The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.


Assuntos
Proteínas E1B de Adenovirus/genética , Proteínas do Capsídeo , Endotélio Vascular/virologia , Neoplasias Experimentais/terapia , Adenoviridae/genética , Antígenos Virais/metabolismo , Capsídeo/metabolismo , Células Cultivadas , Quimioterapia Adjuvante/métodos , Cisplatino/administração & dosagem , Epitélio/virologia , Feminino , Fluoruracila/administração & dosagem , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Injeções Intralesionais , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Transplante de Neoplasias , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/fisiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia
6.
J Clin Invest ; 85(6): 1887-95, 1990 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2189894

RESUMO

Amplification of oncogenes has been found to be an important prognostic factor in behavior of patients' malignancies. In this study we have used new gel electrophoresis techniques to follow the location of amplified c-myc oncogene sequences in HL-60 promyelocytic leukemia cells. In passages 46-62 of the cells, the cells contain amplified c-myc sequences on submicroscopic circular extrachromosomal DNA (episomes). With increased passages in culture (passages 63-72) the cells lose the episome c-myc sequences with a shift of those sequences to double minutes. With additional passage in culture, the c-myc shifts from the double minutes to a chromosomal site der(5)t(5;17)(q11.2;q?11.2). Concomitant with the shift of the c-myc sequences into the chromosomal compartment is a phenotypic change of a shortened cell-doubling time. These studies provide the first molecular evidence of a progression from a submicroscopic location for amplified oncogene sequences to a chromosomal location for the amplified sequences. This molecularly documented model can now be used to test various strategies to prevent incorporation of extrachromosomally located oncogene sequences into chromosomal sites. Prevention of integration of the oncogene sequences into chromosomal sites could modulate progression of patients' tumors.


Assuntos
Aberrações Cromossômicas , DNA de Neoplasias/genética , Amplificação de Genes , Leucemia Promielocítica Aguda/genética , Oncogenes , Plasmídeos , Proteínas Proto-Oncogênicas/genética , Divisão Celular , Humanos , Leucemia Promielocítica Aguda/patologia , Hibridização de Ácido Nucleico , Proteínas Proto-Oncogênicas c-myc , Células Tumorais Cultivadas
7.
Mol Cell Biol ; 9(1): 109-15, 1989 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2648129

RESUMO

Gene amplification in human tumor cells is frequently mediated by extrachromosomal elements (e.g., double minute chromosomes [DMs]). Recent experiments have shown that DMs can be formed from smaller, submicroscopic circular precursors referred to as episomes (S. M. Carroll, M. L. DeRose, P. Gaudray, C. M. Moore, D. R. Needham-Vandevanter, D. D. Von Hoff and G. M. Wahl, Mol. Biol. 8:1525-1533, 1988). To investigate whether episomes are generally involved as intermediates in gene amplification, we determined whether they mediate the amplification of the mdr1 gene, which when overexpressed engenders cross resistance to multiple lipophilic drugs. A variety of methods including electrophoresis of undigested DNAs in high-voltage gradients, NotI digestion, and production of double-strand breaks by gamma irradiation were used to distinguish between mdr1 sequences amplified on submicroscopic circular molecules and those amplified within DMs or chromosomal DNA. The gamma-irradiation procedure provides a new method for detecting and determining the size of circular molecules from 50 kilobases (kb) to greater than 1,000 kb. These methods revealed that some of the amplified mdr1 genes in vinblastine-resistant KB-V1 cells are contained in supercoiled circular molecules of approximately 600 and approximately 750 kb. Analysis of the replication of these molecules by a Meselson-Stahl density shift experiment demonstrated that they replicate approximately once in a cell cycle. The data lend further support to a model for gene amplification in which DMs are generally formed from smaller, autonomously replicating precursors.


Assuntos
Amplificação de Genes , Plasmídeos , Proto-Oncogenes , Sondas de DNA , Replicação do DNA , Resistência a Medicamentos/genética , Eletroforese , Raios gama , Regulação da Expressão Gênica , Humanos , Saccharomyces cerevisiae , Células Tumorais Cultivadas , Vimblastina/farmacologia
8.
Mol Cell Biol ; 8(4): 1525-33, 1988 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2898098

RESUMO

Recent experiments have shown that gene amplification can be mediated by submicroscopic, autonomously replicating, circular extrachromosomal molecules. We refer to those molecules as episomes (S. Carroll, P. Gaudray, M. L. DeRose, J. F. Emery, J. L. Meinkoth, E. Nakkim, M. Subler, D. D. Von Hoff, and G. M. Wahl, Mol. Cell. Biol. 7:1740-1750, 1987). The experiments reported in this paper explore the way episomes are formed and their fate in the cell over time. The data reveal that in our system the episomes are initially 250 kilobases, but gradually enlarge until they become double minute chromosomes. In addition, we show that episomes or double minute chromosomes can integrate into chromosomes. Our results also suggest that episomes can be produced by deletion of the corresponding sequences from the chromosome.


Assuntos
Deleção Cromossômica , Cromossomos/fisiologia , Amplificação de Genes , Genes , Animais , Aspartato Carbamoiltransferase/genética , Carbamoil-Fosfato Sintase (Amônia)/genética , Di-Hidro-Orotase/genética , Cariotipagem , Plasmídeos
9.
Mol Cell Biol ; 7(5): 1740-50, 1987 May.
Artigo em Inglês | MEDLINE | ID: mdl-2885742

RESUMO

In a previous study (G. M. Wahl, B. Robert de Saint Vincent, and M. L. De Rose, Nature (London) 307:516-520, 1984), we used gene transfer of a CAD cosmid to demonstrate that gene position profoundly affects amplification frequency. One transformant, T5, amplified the donated CAD genes at a frequency at least 100-fold higher than did the other transformants analyzed. The CAD genes in T5 and two drug-resistant derivatives were chromosomally located. In this report, we show that a subclone of T5 gives rise to an extrachromosomal molecule (CAD episome) containing the donated CAD genes. Gel electrophoresis indicated that the CAD episome is approximately 250 to 300 kilobase pairs, and a variety of methods showed that it is a covalently closed circle. We show that the CAD episome replicates semiconservatively and approximately once per cell cycle. Since the CAD cosmid, which comprises most of the CAD episome, does not replicate autonomously when transfected into cells, our results indicate that either the process which generated the episome resulted in a cellular origin of DNA replication being linked to the CAD sequences or specific rearrangements within the episome generated a functional origin. The implications of these results for mechanisms of gene amplification and the genesis of minute chromosomes are discussed.


Assuntos
Replicação do DNA , Amplificação de Genes , Genes Reguladores , Complexos Multienzimáticos/genética , Plasmídeos , Proteínas/genética , Animais , Aspartato Carbamoiltransferase/genética , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética , Mapeamento Cromossômico , Cosmídeos , Cricetinae , Enzimas de Restrição do DNA , Di-Hidro-Orotase/genética , Cariotipagem , Transfecção
10.
J Natl Cancer Inst ; 82(2): 96-101, 1990 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-2403594

RESUMO

It is difficult for anyone to determine why oncologists have not paid more attention to the use of in vitro predictive tests in the care of their patients. A review of already completed in vitro-in vivo correlative trials in 2,300 patients indicates percentages of 69 for true positives and 91 for true negatives from predictive assays. These percentages are as good as or better than those seen with already accepted tests, such as estrogen receptor assays or bacterial sensitivity testing systems. Results of a randomized trial of single-agent chemotherapy selections based on a capillary cloning assay versus a clinician's choice indicate the response rate is significantly higher when single-agent chemotherapy is selected by the cloning assay than when it is selected by a clinician (21% vs. 3%). An ongoing randomized trial in which investigators are attempting to corroborate these results in patients with previously untreated small cell lung cancer has been so slow to accrue patients that it is unlikely these trials and others will ever be completed. The usefulness, if any, of these assays and their potential to provide answers to important questions will never be determined unless attitudes are changed about participation in trials. A tool with potential for helping oncologists select patient therapy could be lost unless participation in these trials is obtained.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Valor Preditivo dos Testes , Ensaio Tumoral de Célula-Tronco
11.
J Natl Cancer Inst ; 84(19): 1486-91, 1992 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-1359152

RESUMO

BACKGROUND: Expression of the MDR1 (P-glycoprotein) gene causes resistance to several classes of lipophilic anti-cancer drugs, but MDR1 expression in untreated ovarian and lung carcinomas is rarely detectable by standard assays. PURPOSE: This study was designed to measure the MDR1 messenger RNA (mRNA) content of ovarian and lung carcinomas and to analyze clinical correlations of MDR1 expression in these tumors. METHODS: A sensitive assay based on the polymerase chain reaction (PCR) was used in a retrospective study to measure MDR1 mRNA in biopsy samples of 100 solid tumors, including 60 ovarian and 32 lung carcinomas. The levels of MDR1 mRNA were correlated with history of chemotherapeutic treatment for all tumors; for ovarian and small-cell lung carcinomas (SCLCs), these levels were also correlated with subsequent tumor response to chemotherapy. RESULTS: Among previously untreated patients, MDR1 mRNA was expressed in 68% (50 of 74) of all tumors. Among patients pretreated with chemotherapy regimens that included at least one P-glycoprotein-transported drug (MDR regimens), 95% (20 of 21) of all tumors expressed MDR1 mRNA though the incidence of high-level MDR1 expression was decreased among the treated tumors. MDR1 mRNA was expressed in only one of five tumors treated with regimens that included no P-glycoprotein substrates (non-MDR regimens). Subsequent tumor response to chemotherapy was evaluated in 35 patients with ovarian carcinoma and seven patients with SCLC. The presence of even very low levels of MDR1 mRNA correlated with the lack of response to MDR regimens in these tumor types (P < .035 for ovarian carcinomas, P < .029 for SCLCs, and P < .0005 for both tumor types; Fisher's Exact Test). CONCLUSIONS: Low-level expression of MDR1 mRNA correlates with clinical resistance to combination chemotherapy in ovarian cancer and SCLC. We hypothesize that MDR1 is expressed in a subpopulation of more malignant tumor cells possessing multiple mechanisms of drug resistance. IMPLICATIONS: The presence of MDR1-expressing tumor cells may be useful as a predictive marker for clinical resistance to combination chemotherapy in ovarian cancer and SCLC. Prospective studies are needed to confirm this hypothesis.


Assuntos
Carcinoma/genética , Expressão Gênica , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/análise , Neoplasias Ovarianas/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/secundário , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/secundário , Resistência a Medicamentos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , RNA Neoplásico/análise , Estudos Retrospectivos
12.
J Natl Cancer Inst ; 82(23): 1815-21, 1990 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-2250296

RESUMO

Amplification of the proto-oncogene MYCN (also known as N-myc) in neuroblastomas has been shown to correlate with both disease stage and prognosis, yet little is known about the DNA structures that carry amplified MYCN genes in neuroblastomas in vivo. We have used DNA irradiation and pulsed-field gel electrophoresis to analyze MYCN amplification structures in eight neuroblastomas from separate patients (four primary tumors and four metastatic lesions exhibiting MYCN amplification). Six of the eight neuroblastomas (three primary tumors and three metastatic lesions) exhibited MYCN DNA irradiation profiles consistent with the presence of circular extrachromosomal DNA amplification structures. Five neuroblastomas possessed amplification structures within the size range of double minute chromosomes, and one contained smaller DNA circles. Two neuroblastomas exhibited MYCN DNA irradiation patterns consistent with larger (presumably chromosomal) amplification structures. Multiple sizes of DNA circles were observed in the neuroblastomas of four different patients, implying in vivo multimerization of amplification structures. The presence of circular MYCN amplification structures in six of eight neuroblastomas examined suggests that circular DNA molecules are important structures in in vivo gene amplification.


Assuntos
Amplificação de Genes , Neuroblastoma/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proto-Oncogenes , Southern Blotting , Medula Óssea/patologia , DNA Circular/genética , DNA de Neoplasias/genética , Eletroforese em Gel de Ágar/métodos , Raios gama , Humanos , Cariotipagem , Proto-Oncogene Mas
13.
J Natl Cancer Inst ; 86(8): 608-13, 1994 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-8145276

RESUMO

BACKGROUND: The creatine kinase (CK) isozymes and their substrates, creatine and creatine phosphate, are believed to play a pivotal role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, and brain. This enzyme system may also be involved in the process of cellular transformation. Inhibition of tumor cell growth by creatine analogues has been observed and may be due to the ability of these analogues to impair cellular energy generation and utilization. PURPOSE: An in vitro human tumor colony-forming assay was used to predict the clinical usefulness of creatine analogues as anticancer agents. METHODS: The ability of cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) and homocyclocreatine (1-carboxyethyl-2-iminoimidazolidine) to inhibit the growth of cells prepared from tumor samples taken directly from patients was evaluated by quantitative measurement of colony formation in a soft-agar cell culture assay system. Cyclocreatine was tested in this human tumor colony-forming assay at concentrations ranging from 0.067 to 20 mM against 128 tumor samples, 51 of which formed colonies in the assay and were considered evaluable. Homocyclocreatine was similarly tested at concentrations from 0.2 to 20 mM against 139 tumor samples; 54 were considered evaluable. The colony-forming assay was also used to compare the efficacy of the creatine analogues to representatives from the six major classes of standard chemotherapeutics (alkylating agents, antimetabolites, DNA intercalators, platinum compounds, topoisomerase inhibitors, and tubulin-interacting agents). In addition, CK levels were measured in 192 tumor samples that were taken from 166 patients. RESULTS: Cyclocreatine and homocyclocreatine, at concentrations previously achieved in animal tissues (7-20 mM), had antitumor activity against 19% and 50%, respectively, of tumor samples that formed colonies in the assay. Cyclocreatine was effective against a subset of tumors sensitive to homocyclocreatine (P = .023; Fisher's exact test), which was the more potent creatine analogue in this assay (P < .001; McNemar's test). No relationships were seen between tumor samples sensitive to the creatine analogues and those sensitive to standard chemotherapeutics. Pairwise Wilcoxon rank sum tests indicated that CK activity was significantly higher in tumors with any growth in the colony assay compared with tumors that did not grow (P < .025). CONCLUSIONS: The creatine analogues, cyclocreatine and homocyclocreatine, effectively reduced colony formation of freshly explanted human tumor cells. The mechanism of action or resistance to these compounds seems to differ from those of standard chemotherapeutics. IMPLICATIONS: Creatine analogues that may alter the energy status of the tumor cell potentially represent promising new anticancer agents that function through a unique mechanism.


Assuntos
Antineoplásicos/farmacologia , Creatinina/análogos & derivados , Imidazolidinas , Creatinina/farmacologia , Humanos , Valor Preditivo dos Testes , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
14.
J Natl Cancer Inst ; 86(1): 30-3, 1994 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-8271279

RESUMO

BACKGROUND: Intoplicine (RP60475) is the most active analogue evaluated in the 7H-benzo[e]-pyrido-[4,3-b]-indole series of antineoplastic compounds. It exerts its activity through inhibition of DNA topoisomerase I and II. PURPOSE: This study was planned to determine plasma concentrations of intoplicine necessary for optimal clinical antitumor activity, as well as to pinpoint possible responsive tumor types that can be included in phase II clinical studies. METHODS: Tumor specimens were collected from patients as part of routine clinical measures. Single-cell suspensions were prepared from freshly obtained solid tumor biopsy specimens and were exposed to intoplicine either for 1 hour or continuously. The sensitivity of these specimens to intoplicine was evaluated in a human tumor soft-agar cloning assay. Response was considered positive when the colony-forming unit count in drug-treated samples was 50% or less than the response of control tumor samples treated with saline. RESULTS: With 1-hour exposure to intoplicine at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens showed positive in vitro responses, respectively. With continuous exposure to intoplicine at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively. Activity was seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a intoplicine concentration of 10.0 micrograms/mL after 1-hour exposure. Incomplete cross-resistance with doxorubicin, cisplatin, fluorouracil, 4-hydroperoxycyclophosphamide, vinblastine, and etoposide was also observed. CONCLUSIONS: Intoplicine appears to be active in vitro against a variety of human tumors, including a subgroup of tumors insensitive in vitro to standard antineoplastic compounds. If plasma levels of 10.0 micrograms/mL can be achieved in subjects in ongoing clinical trials, intoplicine could have significant clinical activity. IMPLICATIONS: These data indicate that further investigation of intoplicine is warranted.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , Piridinas/farmacologia , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II , Ensaio Tumoral de Célula-Tronco , Relação Dose-Resposta a Droga , Humanos , Células Tumorais Cultivadas
15.
J Natl Cancer Inst ; 82(2): 110-6, 1990 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-2403593

RESUMO

One hundred thirty-three patients with advanced metastatic cancer were randomized to receive single-agent chemotherapy selected by either a medical oncologist or an in vitro capillary cloning system. Thirty-six of the 65 patients (55%) who were randomly assigned to selection of a drug by the clinician actually received a drug; these patients were able to be evaluated for clinical response. Of these 36 patients, one had a partial tumor response (3%). Only 19 of the 68 patients (28%) who were randomly assigned to selection of a drug by the capillary system actually received a drug; these patients were able to be evaluated for clinical response. Of these 19 patients, four (21%) had partial tumor responses. In the assessable patients (36 in the clinician's choice group, 19 in the capillary cloning group), the partial response rate was superior for drug selection by the capillary cloning system (P = .04). For all patients randomly assigned to a group (65 in the clinician's choice group, 68 in the capillary cloning group), the response rate was not significantly different (1.5% and 5.9%, respectively; P = .37). When overall survival rates for patients in the two groups were compared, there was no difference. We conclude that drug sensitivity testing in capillary tubes can improve the response rate for patients with advanced malignancies. This improved response rate, however, does not translate into improved survival times for these patients.


Assuntos
Antineoplásicos/uso terapêutico , Ensaio de Unidades Formadoras de Colônias , Neoplasias/tratamento farmacológico , Ensaio Tumoral de Célula-Tronco , Humanos , Neoplasias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida
16.
J Natl Cancer Inst ; 84(23): 1816-20, 1992 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-1331485

RESUMO

BACKGROUND: Topotecan [(S)-9-dimethylaminomethyl(10-hydroxy-camptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. PURPOSE: Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. RESULTS: With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 micrograms/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 micrograms/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 micrograms/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. CONCLUSIONS: Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 micrograms/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. IMPLICATIONS: Further clinical development of topotecan is warranted.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Inibidores da Topoisomerase I , Ensaio Tumoral de Célula-Tronco , Camptotecina/farmacologia , Distribuição de Qui-Quadrado , Células Clonais , Humanos , Topotecan , Células Tumorais Cultivadas/efeitos dos fármacos
17.
J Natl Cancer Inst ; 83(2): 124-8, 1991 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-1703237

RESUMO

Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.


Assuntos
Antineoplásicos/uso terapêutico , Flavonoides/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antígenos de Diferenciação/análise , Antígenos de Diferenciação de Linfócitos T/análise , Antígeno CD56 , Avaliação de Medicamentos , Feminino , Flavonoides/efeitos adversos , Flavonoides/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Fc/análise , Receptores de IgG
18.
J Natl Cancer Inst ; 86(19): 1462-5, 1994 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-8089865

RESUMO

BACKGROUND: DMP 840 ((R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]-iso[quinoline-1,3(2H)-dione]dimethane- sulfonate; NSC-D640430) is one in a series of bis-naphthalimides that binds DNA with high affinity and has sequence specificity to multiple G and C bases. It is also a potent inhibitor of RNA synthesis. DMP 840 has been selected for clinical evaluation on the basis of a broad spectrum of activity (including cures) in human tumors in murine models. PURPOSE: We evaluated DMP 840 in a human tumor clonogenic assay to estimate what plasma concentrations may be necessary for clinical cytotoxic activity and to determine what types of tumors potentially might be primary targets for initial phase II studies. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of DMP 840 against cells from biopsy specimens of colorectal, breast, lung ovarian, renal cell, stomach, and bladder cancers and from other tumor types. A total of 260 human tumor specimens were exposed continuously during the assay to DMP 840; 103 were assessable (20 colonies or more on control plates and 30% or less survival for the positive control). An in vitro response was defined as at least a 50% decrease in tumor colony formation resulting from drug exposure compared with controls. RESULTS: In vitro responses were seen in 10% (one of 10), 54% (55 of 101), 80% (82 of 103), and 89% (82 of 92) of specimens tested at 0.01, 0.1, 1.0, and 10.0 micrograms/mL of DMP 840, respectively. At a concentration of 0.1 microgram/mL, specific activity was seen against melanoma (80%) and against renal cell (80%), ovarian (63%), breast (54%), non-small-cell lung (42%), and colorectal cancers (33%). DMP 840 demonstrated activity in tumor specimens resistant in vitro to methotrexate (88%), doxorubicin (58%), platinum (57%), cyclophosphamide (53%), vinblastine (53%), etoposide (53%), fluorouracil (37%), and paclitaxel (36%). CONCLUSIONS: At in vitro concentrations of 0.1 microgram/mL as a continuous exposure, DMP 840 has activity against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. IMPLICATIONS: Further clinical development of DMP 840 is warranted.


Assuntos
Antineoplásicos/farmacologia , Isoquinolinas/farmacologia , Mesilatos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Humanos , Ensaio Tumoral de Célula-Tronco
19.
Cancer Res ; 45(9): 4032-8, 1985 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-3928148

RESUMO

A rapid, semiautomated radiometric system is described for screening for new antineoplastic agents. This radiometric system utilizes inhibition of conversion of [14C]glucose to 14CO2 as an index of cytotoxicity. In this study the radiometric system (BACTEC 460) was first optimized using a variety of human and animal tumor cell lines. Overall, there was a clear linear relationship between the number of cells seeded and the production of 14CO2 from [14C]glucose. The BACTEC System easily detected antitumor activity of compounds from all four classes of antineoplastic agents (doxorubicin, vinblastine, cis-platinum, and methotrexate.) Human tumor cell lines were used to compare the antitumor activity of the same four agents measured by the BACTEC System versus the antitumor activity of the same agents measured by a conventional cloning system. For all cell lines tested there was good agreement in comparison of percentage of survival measured by the BACTEC System versus the standard cloning system. This agreement was better for a continuous exposure to drug in both systems (r = 87, P = less than 0.001) than for a 1-h exposure to the drug (r = 0.35, P = 0.036). In addition to determining the effect of drugs on tumor cells, the BACTEC System was successfully utilized to determine the cytotoxic effect on normal bone marrow buffy coat cells. By utilizing a comparison of suppression of 14CO2 production by normal versus tumor cells, a measurement of differential cytotoxicity could be made. Based on these findings, the radiometric BACTEC System represents a simple and rapid method to detect cytostatic or cytocidal activity of new compounds. It is ideal for use as a prescreen for testing a large number of new chemical entities against a large number of human tumor cell lines.


Assuntos
Antineoplásicos/farmacologia , Ensaio de Unidades Formadoras de Colônias , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaio Tumoral de Célula-Tronco , Dióxido de Carbono/metabolismo , Radioisótopos de Carbono , Linhagem Celular , Glucose/metabolismo , Humanos , Neoplasias/metabolismo , Fatores de Tempo
20.
Cancer Res ; 45(12 Pt 1): 6286-9, 1985 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-4063979

RESUMO

Four statistical techniques are described for comparing the in vitro cytotoxic activity of an analogue and its parent compound in the human tumor cloning system. These techniques include: the Spearman rank correlation coefficient; a sequential pairwise analysis; the kappa statistic for measuring agreement; and the McNemar test of symmetry. These statistical procedures were applied to results from 54 human tumor specimens that were simultaneously tested against multiple concentrations of the Vinca alkaloid vinblastine and its semisynthetic analogue, vinzolidine. Based on the percentage of survival of tumor colony-forming units in the human tumor cloning system, vinzolidine was shown to have a 26% in vitro response rate with a spectrum of activity across major tumor types. However, all four statistical procedures indicated that the activity of vinzolidine was not superior to that of its parent compound. Of the four statistical procedures examined, the sequential pairwise design appears to be best suited for comparing in vitro activity of an analogue and its parent compound and could result in a savings of both time and resources required for such comparisons.


Assuntos
Células-Tronco Neoplásicas/efeitos dos fármacos , Vimblastina/farmacologia , Alcaloides de Vinca/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Modelos Biológicos , Neoplasias Experimentais/patologia , Estatística como Assunto , Relação Estrutura-Atividade
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