Abstract:
:We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 micrograms/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 micrograms/kg/min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 mumol/liter at the initiation of the infusion to a median of 40.4 mumol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/kg. The area under the concentration x time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Erlichman C,Moore M,Thiessen JJ,Kerr IG,Walker S,Goodman P,Bjarnason G,DeAngelis C,Bunting Psubject
Has Abstractpub_date
1993-10-15 00:00:00pages
4837-42issue
20eissn
0008-5472issn
1538-7445journal_volume
53pub_type
临床试验,杂志文章相关文献
CANCER RESEARCH文献大全abstract::Histone deacetylase (HDAC) inhibitors are undergoing clinical evaluation for cancer therapy. Because HDAC modulates chromatin structure and gene expression, parameters considered to influence radioresponse, we have investigated the effects of the HDAC inhibitor MS-275 on the radiosensitivity of two human tumor cell li...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.can-03-2630
更新日期:2004-01-01 00:00:00
abstract::Hypomethylation of CpG dinucleotides in genomic DNA was one of the first somatic epigenetic alterations discovered in human cancers. DNA hypomethylation is postulated to occur very early in almost all human cancers, perhaps facilitating genetic instability and cancer initiation and progression. We therefore examined t...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-6088
更新日期:2008-11-01 00:00:00
abstract::To prevent their recognition as DNA breaks, the ends of linear chromosomes are organized into telomeres, which are made of proteins bound to telomere-specific, double-stranded repeats and to single-stranded DNA extensions, the G-tails. The mammalian heterogeneous nuclear ribonucleoparticule A1 and A2 proteins can bind...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-11-15 00:00:00
abstract::The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappaB (NF-kappaB) via IkappaBalpha phosphorylation. I...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-2272
更新日期:2007-02-15 00:00:00
abstract::Spheroids derived from the human bladder cancer cell line MGH-U1 were initiated in spinner culture and then transferred to multiwell plates which contained medium with varying concentrations of glucose and pyruvate. Growth of individual spheroids was monitored, and at different times after transfer spheroids were sect...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-06-01 00:00:00
abstract::The effects of temperature in the fever range (37-42 degrees) on the membrane potentials of normal and simian virus 40-transformed hamster lymphocytes were analyzed. The transmembrane distributions of radiolabeled triphenylmethylphosphonium and thiocyanate were measured, and they provide upper and lower limits for the...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-01-01 00:00:00
abstract::We have analyzed the mechanism of activation of two human ras oncogenes. We have also identified a rasN gene from a human gastric adenocarcinoma which efficiently induced both morphological transformation and tumorigenicity of NIH3T3 cells in a transfection assay. The rasN gene in tumor tissue DNA did not appear to be...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::Aluminum sulfonated phthalocyanine has potential as a suitable photosensitizer for use in the photodynamic therapy of cancer. In the present study, cellular uptake and retention of the individual mono-, di-, tri-, and tetrasulfonated derivatives (AlS1-4Pc) were examined in tissue culture and in normal and neoplastic t...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract::Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development....
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-13-2921-T
更新日期:2014-02-15 00:00:00
abstract::Genetic instability, a hallmark feature of human cancers including prostatic adenocarcinomas, is considered a driver of metastasis. Somatic copy number alterations (CNA) are found in most aggressive primary human prostate cancers, and the overall number of such changes is increased in metastases. Chromosome 10q23 dele...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-3280
更新日期:2016-01-15 00:00:00
abstract::9-beta-D-Arabinofuranosyladenine (ara-A) is an inhibitor of DNA replication with antitumor and antiviral activity. The molecular basis for this inhibitory effect has remained unclear. The present work has examined the effects of 9-beta-D-arabinofuranosyladenine-triphosphate on DNA polymerase-beta. These studies were p...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-04-15 00:00:00
abstract::Although peptide immunization often leads to the induction of strong T-cell responses, it is seldom effective against established tumors. One possibility is that these T-cell responses are not strong enough or do not last sufficiently long to have an effect in tumor eradication. Here, we examined the role of synthetic...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-06-15 00:00:00
abstract::Successive B16 melanoma tumor lines were selected for their ability to form pulmonary tumor nodules. This was accomplished by injecting tumor cells i.v. into syngeneic C57BL/6 mice and 2 to 3 weeks later collecting the secondary tumor growths and placing them into tissue culture. These tumor cells were then injected i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1975-01-01 00:00:00
abstract::Angiogenesis is essential for the growth of solid tumors. We have observed previously that the vascular endothelial cells of astrocytic brain tumors express human telomerase reverse transcriptase (hTERT) mRNA, suggesting a role for telomerase in the angiogenesis of these neoplasms. Here, we used an in vitro model to d...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2003-07-01 00:00:00
abstract::In this study, we have exploited the power of insertional mutagenesis to elucidate tumor progression pathways in mice carrying two oncogenes (MYC/Runx2) that collaborate to drive early lymphoma development. Neonatal infection of these mice with Moloney murine leukemia virus resulted in accelerated tumor onset with ass...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-0433
更新日期:2007-06-01 00:00:00
abstract::Partially purified preparations of mouse interferon, administered during the 2-day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from mortality in BALB/c X DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon induce...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-02-01 00:00:00
abstract::Epidermal growth factor receptor vIII (EGFRvIII) is a tumor-specific, ligand-independent, constitutively active variant of the EGFR. Its expression has been detected in gliomas and various other human malignancies. To more fully characterize the function and potential biological role of EGFRvIII in regulating cell pro...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2000-06-01 00:00:00
abstract::FoxP3 is a member of the forkhead family of transcription factors critically involved in the development and function of CD25(+) regulatory T cells (Treg). Until recently, FoxP3 expression was thought to be restricted to the T-cell lineage. However, using immunohistochemistry and flow cytometric analysis of human mela...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-5664
更新日期:2008-04-15 00:00:00
abstract::The expression of genes involved in p53-mediated apoptosis was studied using cDNA microarray after treating isogenic cell lines with either ionizing radiation or doxorubicin. Most of the known p53 transcriptional activation target genes clustered in a functional category defined by early and p53-dependent induction, r...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-09-15 00:00:00
abstract::Both activating and inactivating mutations in protein tyrosine phosphatase Ptpn11 (encoding Shp2) are associated with tumorigenesis. However, the underlying mechanisms remain unclear. Here, we show that Shp2 plays an important role in mitosis, dysregulation of which results in chromosome instability and cancer predisp...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-12-1495
更新日期:2012-10-15 00:00:00
abstract::We have identified RGS17 as a commonly induced gene in lung and prostate tumors. Through microarray and gene expression analysis, we show that expression of RGS17 is up-regulated in 80% of lung tumors, and also up-regulated in prostate tumors. Through knockdown and overexpression of RGS17 in tumor cells, we show that ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-3495
更新日期:2009-03-01 00:00:00
abstract::For two decades, the antigen recognized by the Pathologische Anatomie Leiden-Endothelium (PAL-E) monoclonal antibody, a standard vascular endothelial cell marker, has remained elusive. Here, we used a combinatorial phage display-based approach ("epitope mapping") to select peptides binding to the original PAL-E antibo...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-2737
更新日期:2007-10-15 00:00:00
abstract::Copper plays an essential role in promoting angiogenesis. Tumors that become angiogenic acquire the ability to enter a phase of rapid growth and exhibit increased metastatic potential, the major cause of morbidity in cancer patients. We report that copper deficiency induced by tetrathiomolybdate (TM) significantly imp...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-09-01 00:00:00
abstract::A monoclonal antibody (5E8) has been used to identify and structurally characterize a previously unreported macromolecule present on the surface of human lung tumors. This antibody was derived from a hybrid clone that was produced using spleen cells of mice immunized with a surgically excised squamous cell carcinoma. ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::Three human colon cancer lines (SW 480, SW 620, WIDR) were characterized as to their production of molecules with transforming growth factor (TGF)-like activity. Production of both TGF alpha-like and TGF beta-like activity was quantitated, as were cellular receptors for these molecules, and growth response in soft aga...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::Organic anion transporting polypeptide 1B3 (OATP1B3, SLCO1B3) is normally expressed in hepatocytes. In this study, we showed frequent overexpression of OATP1B3 in colorectal adenocarcinomas. Quantitative reverse transcription-PCR analysis of 17 colon tumors indicated tumoral overexpression of OATP1B3 by approximately ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-1984
更新日期:2008-12-15 00:00:00
abstract::The conversion of transforming growth factor beta (TGF-beta) from a tumor suppressor to a tumor promoter occurs frequently during mammary tumorigenesis, yet the molecular mechanisms underlying this phenomenon remain undefined. We show herein that TGF-beta repressed nuclear factor-kappaB (NF-kappaB) activity in normal ...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-3094
更新日期:2008-03-01 00:00:00
abstract::The development of androgen-independent growth in advanced carcinoma of the prostate (CaP) is associated with poor prognosis and few therapeutic options. Chemotherapeutic drugs offer the afflicted patient palliative benefits, but these are short-lived because of the chemoresistant nature of hormone-refractory prostate...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-1612
更新日期:2004-11-15 00:00:00
abstract::We have shown that cyclophosphamide (CY) can augment the development of delayed-type hypersensitivity to a primary antigen in patients with advanced cancer. In the present study, we administered CY (1000 mg/sq m) to 19 patients with advanced, metastatic cancer and monitored the compositional and functional changes in ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1984-03-01 00:00:00
abstract::Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as me...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-14-2089
更新日期:2015-04-15 00:00:00