Abstract:
:Inhibition of cellular DNA synthesis is the major action of gemcitabine. In cells, this drug is converted to its triphosphate (dFdCTP), which is incorporated into DNA and terminates DNA strand elongation. After incorporation of gemcitabine nucleotide into the DNA strand, one more deoxynucleotide is incorporated, and thereafter the DNA polymerases are unable to proceed ("masked chain termination"). Gemcitabine also inhibits DNA synthesis indirectly by decreasing cellular dNTP pools via inhibition of ribonucleotide reductase. Incubation of human leukemia cells (CEM) with gemcitabine leads to apoptotic cell death. Two types of DNA fragmentation were observed in the gemcitabine-treated cells: (1) large-sized double-stranded DNA fragments range from 5 kb to 500 kb with the majority of the fragments located at 50 kb, and (2) nucleosomal-sized DNA fragments. Both types of drug-induced DNA fragmentation were detected in exponentially growing cells and were much more prominent in cells synchronized at S phase. The gemcitabine-induced DNA fragmentation in either synchronized or nonsynchronized cells was inhibited by the DNA synthesis inhibitor, aphidicolin. Thus, incorporation of gemcitabine into DNA is essential to induce DNA fragmentation. The intracellular calcium chelator BAPTA-AM inhibited the drug-induced nucleosomal DNA fragmentation but did not prevent the large-sized DNA fragmentation, suggesting that the nucleosomal DNA fragmentation is a calcium-dependent event, whereas the large-sized DNA fragmentation is independent of calcium. Furthermore, BAPTA-AM did not prevent the morphologic appearance of apoptotic bodies in cells incubated with gemcitabine, indicating that degradation of DNA to nucleosomal fragments is not an essential element of the apoptotic process. Phorbol 12-myristate 13-acetate also inhibited drug-induced nucleosomal DNA fragmentation, but prevented neither large-sized DNA fragmentation nor formation of apoptotic bodies. In contrast, aphidicolin inhibited both types of DNA fragmentation and blocked the formation of apoptotic bodies in the presence of gemcitabine. These data suggest that the generation of large-sized DNA fragments caused by incorporated gemcitabine monophosphate in DNA is critical in gemcitabine-induced apoptosis, whereas nucleosomal DNA fragmentation is not a requirement in this cell death process.
journal_name
Semin Oncoljournal_title
Seminars in oncologyauthors
Huang P,Plunkett Wsubject
Has Abstractpub_date
1995-08-01 00:00:00pages
19-25issue
4 Suppl 11eissn
0093-7754issn
1532-8708journal_volume
22pub_type
杂志文章abstract::Solid malignancies often exhibit high interstitial fluid pressure (IFP), which causes poor uptake of anticancer drugs. While there are several mechanisms that regulate IFP in tumors, activation of platelet-derived growth factor receptor, which is expressed in various cell types within the tumor microenvironment, has b...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/j.seminoncol.2004.03.036
更新日期:2004-04-01 00:00:00
abstract::Evidence published during several decades has shown that there is a group of epithelial ovarian tumors having histological and biological features between those of clearly benign and frankly malignant tumors. In 1963, FIGO accepted an intermediate group of ovarian carcinomas of low malignant potential. In 1973, WHO ad...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1998-06-01 00:00:00
abstract::In a significant fraction of patients with NHL, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and BMT is expanding. Remissions can be achieved in many patients with refractory NHL in particular those patients with tumors that are still ch...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1990-02-01 00:00:00
abstract::Lonidamine belongs to a new class of antineoplastics agents, since it does interfere with cell energy processes. When administered as single agent in metastatic breast cancer, it produces moderate therapeutic effects. The pattern of toxicity includes myalgias, asthenia, testicular pain, and gastrointestinal discomfort...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1991-04-01 00:00:00
abstract::The Department of Veterans Affairs (VA) has a strong track record providing high-quality, evidence-based care to cancer patients. In order to accelerate discoveries that will further improve care for Veterans with cancer, the VA has partnered with the Center for Translational Data Science at the University of Chicago ...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:10.1053/j.seminoncol.2019.09.002
更新日期:2019-01-01 00:00:00
abstract::Colorectal cancer is an ideal model in which to study malignant progression from the molecular-genetic perspective because different stages of the same malignancy coexist within each patient. Approximately 75% of colorectal cancer cases are sporadic and the remaining are familial disease, yet genetic mutations that ha...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/j.seminoncol.2006.10.003
更新日期:2006-12-01 00:00:00
abstract::32P orthophosphate administered in a wide range of activity reduces or relieves the pain from osteoblastic metastases in approximately 80% of patients treated. The efficacy of this agent is equal to that of newer agents and of wide field radiotherapy, as documented in a literature review of 28 series reporting the use...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1993-06-01 00:00:00
abstract::Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:10.1053/sonc.2002.30152
更新日期:2002-02-01 00:00:00
abstract::Although bone and soft tissue sarcomas are not common, a significant number of patients who develop these tumors will die with metastatic disease. Part of the reason is that many of the patients have advanced disease at diagnosis. Identification of an etiologic agent should allow for diagnosis at an earlier stage. Thi...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1989-08-01 00:00:00
abstract::High-dose interferon alfa (IFN alfa) therapy induces an overall response rate of 25% to 30% in unselected patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Up to 50% of patients with relatively preserved immune reactivity respond to treatment. However, when dosages of 20 x 10(6) units o...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1990-02-01 00:00:00
abstract::An overview of the causes, the clinical pictures and the management of obstruction in three major organ systems due to primary and secondary malignant neoplasms has been presented. Such obstruction often produces dramatic clinical pictures that require careful, appropriate, and often aggressive therapy if patients are...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1978-06-01 00:00:00
abstract::The consistently high mortality rates associated with gastrointestinal cancer result in large part from malignancies that progress undetected to an advanced stage of disease when treatment is usually less effective. In response to this fact, increasing attention has been directed toward developing methods of both prim...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1991-02-01 00:00:00
abstract::Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) displays nonlinear pharmacokinetics in humans. Both peak plasma paclitaxel concentrations and areas under the curve (AUCs) of the concentration versus time profiles will change disproportionately to changes in dose. Models that accurately describe the pla...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1995-06-01 00:00:00
abstract::The evaluation of the activity of new drugs against small cell lung cancer (SCLC) is discussed and the results with gemcitabine are presented. Gemcitabine has activity against untreated SCLC. Preliminary results from an ongoing study also indicate activity in so-called resistant SCLC. ...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1998-08-01 00:00:00
abstract::Breast cancer patients undergoing therapeutic regimens of high-dose chemotherapy (HDCT) with circulating progenitor cell support often develop anemia. As a general consideration in the transplantation setting, red blood cell transfusions are normally required in patients who have passed the myeloablative phase after H...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/sonc.2002.33529
更新日期:2002-06-01 00:00:00
abstract::Multitargeted antifolate (MTA, LY231514) is a novel antifolate antimetabolite, with antitumor activity via inhibition of thymidylate synthase, glycinamide formyl transferase, and dihydrofolate reductase. Three dosing schedules have been investigated in the phase I setting: daily x5 every 21 days, weekly x4 every 42 da...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1999-04-01 00:00:00
abstract::The acute tumor lysis syndrome (ATLS) is characterized by the rapid development of hyperuricemia, hyperkalemia, hyperphosphatemia, and acute renal failure (ARF). Hematologic malignancies are responsible for most cases of ATLS. Control of hyperuricemia and the achievement of a high urine flow are the mainstays of preve...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:2000-06-01 00:00:00
abstract::Basket clinical trials are a new category of early clinical trials in which a treatment is evaluated in a population of patients with tumors of various histologic types and primary sites selected for containing specific genomic abnormalities. The objective of such studies is generally to discover histologic types in w...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:10.1053/j.seminoncol.2016.01.002
更新日期:2016-02-01 00:00:00
abstract::Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor family, which produces factors that are considered to be important mediators of cell growth. Overexpression of HER2, which occurs in approximately 25% to 30% of human breast cancers, has fostered considerable interest i...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:
更新日期:1999-08-01 00:00:00
abstract::Many cytotoxic therapies are available for patients with metastatic breast cancer, but response rates are low and acquired or de novo resistance is virtually universal. Among the agents that are used in the treatment of pretreated metastatic breast cancer are vinorelbine, gemcitabine, nab-paclitaxel, pemetrexed, plati...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/j.seminoncol.2011.04.005
更新日期:2011-06-01 00:00:00
abstract::Investigators representing all major melanoma research areas present an overview of the most important challenges for the field. Four major research areas are covered plus the training of new investigators. For each area we first describe the present status, its strengths and weaknesses, and then outline specific reco...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:10.1053/j.seminoncol.2007.09.004
更新日期:2007-12-01 00:00:00
abstract::Two children with biopsy-proven LCH underwent successful hepatic transplantation for end-stage liver disease. These patients were thought not to have active LCH disease at the time of transplantation, although one had developed a new osteolytic lesion a few months before the operation and the other had suspicious oste...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:
更新日期:1991-02-01 00:00:00
abstract::Therapy for metastatic breast cancer can palliate disease and prolong life, but cannot cure. New drugs will be required if this is to change. Cisplatin and its analogue carboplatin offer new approaches to the treatment of metastatic breast cancer. Cisplatin has significant single-agent, front-line activity in metastat...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1992-02-01 00:00:00
abstract::Many patients with Hodgkin's and non-Hodgkin's lymphoma (NHL) can be cured today with combination chemotherapy and/or radiotherapy. However, for patients with suboptimal responses to initial therapy or for patients with refractory or relapsed disease, salvage therapy alone is usually inadequate to achieve long-term su...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1998-08-01 00:00:00
abstract::Hypercalcemia of malignancy (HCM) is a potentially life-threatening complication of cancer resulting from increased bone resorption by osteoclasts. Clinical management of HCM primarily consists of intravenous rehydration therapy combined with pharmaceutical agents that decrease osteoclast activity. Several generations...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/sonc.2002.37417
更新日期:2002-12-01 00:00:00
abstract::We report an update on a prospective observational trial for Waldenstrom's macroglobulinemia (WM) that called for re-registration to treatment with fludarabine (30 mg/m(2)) upon the development of symptomatic or progressive disease. Patients who did not require therapy for more than 1 year (n = 54) could be distinguis...
journal_title:Seminars in oncology
pub_type: 临床试验,杂志文章
doi:10.1053/sonc.2003.50050
更新日期:2003-04-01 00:00:00
abstract::Phase I studies of CPT-11 (irinotecan) have been conducted in Europe, the United States, and Japan to determine the maximum tolerated dose (MTD) and the most appropriate intravenous administration schedule for further evaluation in phase II investigations. Diarrhea and/or neutropenia were the major dose-limiting toxic...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:
更新日期:1996-02-01 00:00:00
abstract::Epigenetic alterations play a pivotal role in cancer development and progression. Pharmacologic reversion of such alterations is feasible, and second generation "epigenetic drugs" are in development and have been demonstrated to possess significant immunomodulatory properties. This knowledge, together with the availab...
journal_title:Seminars in oncology
pub_type: 杂志文章,评审
doi:10.1053/j.seminoncol.2015.02.003
更新日期:2015-06-01 00:00:00
abstract::In a multicenter phase III trial, 267 patients with nonbulky metastatic colorectal cancer who had failed first-line 5-fluorouracil (5-FU) therapy were randomized to receive second-line treatment with either the new topoisomerase agent, irinotecan (Rhône-Poulenc Rorer, Antony, France), or a high-dose infusional 5-FU re...
journal_title:Seminars in oncology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:1999-02-01 00:00:00
abstract::We resected 158 cases of hepatocellular carcinoma (HCC), including 20 (12.6%) cases of large HCC. These 20 cases were divided into group 1 (curative resection, n = 9) and group 2 (noncurative resection, n = 11). The clinicopathologic features and long-term survival of the cases were evaluated. In groups 1 and 2, porta...
journal_title:Seminars in oncology
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00