Abstract:
:Clinically available taxanes represent one of the most promising class of antitumor agents, despite several problems with their solubility and toxicity. In an attempt to improve the pharmacological profile of taxanes, a new series of analogues was synthesized from 14beta-hydroxy-10-deacetylbaccatin III and tested in a panel of human tumor cell lines. On the basis of the pattern of cytotoxicity and lack of cross-resistance in tumor cell lines expressing the typical multidrug-resistant phenotype, a compound (IDN5109) was selected for preclinical development. A comparative efficacy study of IDN5109 and paclitaxel was performed using a large panel of human tumor xenografts, characterized by intrinsic (seven tumors) or acquired (four tumors) resistance to cisplatin or doxorubicin, including four ovarian, one breast, one cervical, three lung, one colon, and one prostatic carcinoma. Drugs were delivered i.v. according to the same schedule (four times every 4th day). IDN5109 achieved a very high level of activity (percentage tumor weight inhibition >70%; log10 cell kill >1) in all but one of the tested tumors. Compared to paclitaxel, IDN5109 exhibited a significantly superior activity in six tumors (including the four tumors that were resistant to paclitaxel) and a comparable activity against the other five paclitaxel-responsive tumors. Additional advantages of IDN5109 over paclitaxel were also suggested by its toxicity profile. IDN5109 was not only less toxic (maximal tolerated doses were 90 and 54 mg/kg for IDN5109 and paclitaxel, respectively), but it also appeared to be endowed with a reduced neurotoxic potential and an improved profile of tolerability compared to the parent drug. Furthermore, the best antitumor efficacy was often already reached with doses lower than the maximal tolerated dose, suggesting an improved therapeutic index for the new drug. In conclusion, the results support the preclinical interest of IDN5109 in terms of the toxicity profile and of the efficacy with particular reference to the ability to overcome multiple mechanisms of drug resistance.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Polizzi D,Pratesi G,Tortoreto M,Supino R,Riva A,Bombardelli E,Zunino Fsubject
Has Abstractpub_date
1999-03-01 00:00:00pages
1036-40issue
5eissn
0008-5472issn
1538-7445journal_volume
59pub_type
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::Multiple tobacco smoke-related premalignant and malignant lesions develop synchronously or metachronously in various organ sites, including the oral cavity. Both field cancerization and clonal migration seem to contribute to the occurrence of multiple tumors. Although the importance of endogenous factors (e.g., oncoge...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1388
更新日期:2007-09-15 00:00:00
abstract::Bisphosphonate (BP), a specific inhibitor of osteoclasts, has been widely used as a beneficial agent for the treatment of bone metastases in patients with breast cancer. It is well recognized that BP reduces osteolysis by promoting apoptosis in osteoclasts. However, recent animal and human data suggest that BPs not on...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-06-01 00:00:00
abstract::The interleukin (IL)-13 receptor alpha2 (IL-13Ralpha2) chain is a primary binding and internalization subunit for a Th2-derived immune regulatory cytokine, IL-13. Although extremely high levels of IL-13Ralpha2 chain are expressed on a variety of human tumor cells and specimens, its precise role in tumor immunology has...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-1265
更新日期:2006-04-15 00:00:00
abstract::The D98/AH-2 cell line (a subline of HeLa) expresses a form of alkaline phosphatase (ALP) which closely resembles the adult and fetal intestinal forms of ALP. To characterize this ectopic form of ALP, four monoclonal antibodies were raised against D98/AH-2 ALP, and their binding with ALPs from D98/AH-2 cells, placenta...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1983-02-01 00:00:00
abstract::Suspensions of an oxygen-sensitive (MT-7) and of an oxygen-insensitive(M109) tumor cell line were injected i.v. into BALB/c mice. Exposure to 100% O2 after injection of the cells did not modify the initial arrest of either cell line in the lung. Exposure of animals given injections of MT-7 cells for 60 h to 100% oxyge...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-05-15 00:00:00
abstract::G3361/CP cells, a cisplatin (CDDP)-resistant subclone of the human melanoma cell line G3361, overexpress wild-type p53 protein and demonstrate an increase in the percentage of cells in G0--G1 arrest compared to parental cells. Exposing G3361/CP cells to human recombinant IFN-alpha2a reduces the high basal levels of p5...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
abstract::Although ethanol has generally not been found to induce cancer in experimental animals, the consumption of alcoholic beverages has been linked to increased risks of several cancers in humans. Risks of oral, pharyngeal, laryngeal, esophageal, and liver cancer are elevated among drinkers, typically in proportion to the ...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:
更新日期:1992-04-01 00:00:00
abstract::The conditions for growing preneoplastic mammary epithelial cells in primary cell cultures with serum-free factor-defined medium were established in a series of experiments. The cells, grown in Dulbecco's modified Eagle's medium with 0.6 mM Ca2+, epidermal growth factor, transferrin, insulin, and Na2SeO3, were fibrobl...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1980-11-01 00:00:00
abstract::In previous studies, we reported that key antioxidant and DNA repair genes are regulated differently in normal bronchial epithelial cells of lung cancer cases compared with non-lung cancer controls. In an effort to develop a biomarker for lung cancer risk, we evaluated the transcript expressions of 14 antioxidant, DNA...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-1568
更新日期:2009-11-15 00:00:00
abstract::To analyze the humoral immune response to melanoma, human-mouse hybridomas were generated by the fusions of regional lymph node lymphocytes of patients with the mouse myeloma cell line M5. Six stable hybridomas were cloned from six separate lymphocyte parents obtained from three patients. Ascites were obtained from nu...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-05-01 00:00:00
abstract::Anti-idiotypic monoclonal antibodies (MoAbs) were prepared in a syngeneic system against anti-carcinoembryonic antigen (CEA) MoAb 5B3 (IgG1), which reacted with a carbohydrate moiety on CEA, and MoAb MA208 (IgG1), which reacted with a peptide on CEA. Anti-idiotypic MoAb T3-503 and T4-202 recognized the private idiotyp...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-05-15 00:00:00
abstract::Cancer stem-like cells (CSC) in hepatocellular carcinoma (HCC) are thought to mediate therapeutic resistance and poor survival outcomes, but their intrinsic and extrinsic control is not well understood. In this study, we found that the chromatin modification factor LSD1 is highly expressed in HCC CSC where it decrease...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-17-1236
更新日期:2018-02-15 00:00:00
abstract::Activities of the adenine purine nucleotide cycle enzymes, i.e., adenylosuccinate (SAMP) synthetase, SAMP lyase, and adenosine 5'-monophosphate deaminse, were determined in hepatic tissue of rats fed and/or given injections of 3'-methyl-4-dimethylaminoazobenzene, 4'-methyl-4-dimethylaminoazobenzene, thioacetamide, eth...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1979-06-01 00:00:00
abstract::The olfactory marker protein (OMP) is a M(r) 19,000 polypeptide originally considered a selective marker for differentiated olfactory receptor neurons. In an attempt to induce neoplastic proliferation in the olfactory cells, we made mice transgenic for the simian virus 40 large T-antigen gene linked to the OMP gene pr...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
abstract::Liposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with un...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-05-4007
更新日期:2006-03-15 00:00:00
abstract::To assess the in vivo behavior of cytotoxic agents linked to antibodies, deferoxamine, known to form stable chelates with 67Ga, was conjugated with monoclonal antibodies using three different methods. One method used a homocoupling reagent, glutaraldehyde, whereas two other methods used heterocoupling reagents, N-succ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1988-03-01 00:00:00
abstract::Metabolic activation may be a key step in determining the tissue specificity of carcinogenic nitrosamines. In previous work, we characterized P450IIE1 (an acetone/ethanol-inducible form of cytochrome P-450) as the major enzyme for the metabolic activation of N-nitrosodimethylamine. In this work, we investigated the me...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-03-15 00:00:00
abstract::Defects in antitumor immune responses have been associated with increased release of prostaglandin E(2) (PGE(2)) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE(2) on antitumor CD8(+) T-cell responses generated both by cross-presenting dendritic cells an...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-1060
更新日期:2008-09-15 00:00:00
abstract::Irinotecan hydrochloride (CPT-11), an antitumor camptothecin derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major m...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1996-08-15 00:00:00
abstract::Many tumor types have p53 and/or RB mutations, and it is unclear what role the mutations of these tumor suppressor genes have on the efficacy of chemotherapeutic agents. The effect of p53 and RB inactivation on sensitivity to chemotherapeutic drugs was examined using a model system in which p53 or RB was inactivated i...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1996-02-15 00:00:00
abstract::Soluble membrane fractions derived from polyoma tumor cells trigger lymphocytes, derived from polyoma-immunized animals, but not from nonimmunized controls, to release the lymphokine, macrophage migration-inhibitory factor. The reaction can be blocked by sera from polyoma-bearing animals. Absorption of these sera with...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::Studies demonstrate that some colon cancers possess receptors for various gastrointestinal hormones or neurotransmitters, the occupation of which can affect growth. These results are limited because frequently only a small number of tumors are studied, only 1 or 2 receptors are sought, and the effect on cell function ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1992-03-01 00:00:00
abstract::Genomic imprinting is an epigenetic modification of the gamete or zygote leading to parental origin-specific gene expression in somatic cells of the offspring. We have previously identified a cluster of imprinted genes on human chromosome 11p15.5, a region involved in Beckwith-Wiedemann syndrome, Wilms' tumor, and ova...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1998-03-01 00:00:00
abstract::Murine sarcoma virus (Moloney strain) (MSV-M)-induced tumors are unusual in that they regularly appear less than 2 weeks after virus inoculation, progress for 1 to 2 weeks, and are rejected by normal adult BALB/c mice. Rejectio leaves the animals immune to tumor induction. In the present study, presensitization of nor...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1976-12-01 00:00:00
abstract::The FGFR1 gene transcript is alternatively processed to produce functionally different receptor forms. Previously, we identified a 69-nucleotide exonic splicing enhancer (ESE) required for alpha-exon inclusion in JEG3 cells. In the present study, we found that this sequence is composed of three independent elements, t...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-0716
更新日期:2004-12-15 00:00:00
abstract::Frontline anticancer therapies such as chemotherapy and irradiation often slow tumor growth, but tumor regrowth and spread to distant sites usually occurs after the conclusion of treatment. We recently showed that macrophages could be used to deliver large quantities of a hypoxia-regulated, prostate-specific oncolytic...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-12-3056
更新日期:2013-01-15 00:00:00
abstract::The antitumor effects of methotrexate with 5-fluorouracil against the Sarcoma 180 mouse tumor model were found to be schedule dependent. Pretreatment of tumor-bearing animals with methotrexate significantly enhanced the antitumor activity of the combination relative to simultaneous treatment or to those with methotrex...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1977-01-01 00:00:00
abstract::Compelling evidences indicate a key role for regulatory T cells (T(reg)) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effec...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-0050
更新日期:2008-08-01 00:00:00
abstract::An in vivo model of human CD20+ B-lymphoma was established in severe combined immunodeficiency mice to test the ability of human neutralizing miniantibodies to CD55 and CD59 (MB55 and MB59) to enhance the therapeutic effect of rituximab. The miniantibodies contained single-chain fragment variables and the hinge-CH2-CH...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-1811
更新日期:2007-11-01 00:00:00