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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinically effective cancer immunotherapy has been sought for more than 100 years and has been recently applied most successfully in strategies that passively deliver immune effectors such as monoclonal antibodies (anti-CD20 for lymphoma and anti-HER2/neu for breast cancer), donor lymphocyte infusions in chronic myelongenous leukemia and non-myeloablative allogeneic peripheral blood progenitor transplants for renal cell carcinoma. There is mounting enthusiasm for strategies employing active stimulation of antitumour immune responses. These include vaccines based on tumour antigen proteins and peptides, autologous, allogeneic or gene-modified tumour cells, dendritic cells and antigen-encoding viral vector constructs. Indeed, randomised Phase III clinical trials of autologous tumour cell vaccines for colorectal cancer demonstrated an improvement in disease free survival and a trend toward improved overall survival [1]. Despite these preliminary successes, it is clear that the many strategies under development cannot all be evaluated for survival benefit in large clinical trials that require many years, patients and resources to complete. This highlights the need to develop intermediate markers to help prioritise which agents to test in prospective randomised Phase III trials.
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PMID:Surrogate markers of response to cancer immunotherapy. 1172 26

Replication-competent murine leukemia virus (MLV) vectors can be engineered to achieve high efficiency gene transfer to solid tumors in vivo and tumor-restricted replication, however their safety can be further enhanced by redirecting tropism of the virus envelope. We have therefore tested the targeting capability and replicative stability of ecotropic and amphotropic replication-competent retrovirus (RCR) vectors containing two tandem repeats from the immunoglobulin G-binding domain of Staphylococcal protein A inserted into the proline-rich "hinge" region of the envelope, which enables modular use of antibodies of various specificities for vector targeting. The modified envelopes were efficiently expressed and incorporated into virions, were capable of capturing monoclonal anti-HER2 antibodies, and mediated efficient binding of the virus-antibody complex to HER2-positive target cells. While infectivity was markedly reduced by pseudotyping with targeted envelopes alone, coexpression of wild-type envelope rescued efficient cellular entry. Both ecotropic and amphotropic RCR vector/anti-HER2 antibody complexes achieved significant enhancement of transduction on murine target cells overexpressing HER2, which could be competed by preincubation with excess free antibodies. Interestingly, HER2-expressing human breast cancer cells did not show enhancement of transduction despite efficient antibody-mediated cell surface binding, suggesting that target cell-specific parameters markedly affect the efficiency of post-binding entry processes. Serial replication of targeted vectors resulted in selection of Z domain deletion variants, but reduction of the overall size of the vector genome enhanced its stability. Application of antibody-mediated targeting to the initial localization of replication-competent virus vectors to tumor sites will thus require optimized target selection and vector design.
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PMID:Antibody-mediated targeting of replication-competent retroviral vectors. 1280 41

The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function.
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PMID:[New immunological weapons for medicine in the 21st Century: biological therapy based on the use of the latest generation monoclonal antibodies]. 1502 9

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2-regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile of ERBB2-transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genome wide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)
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PMID:Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis. 1560 25

Members of a novel series of pyrrolo-1,5-benzoxazepine (PBOX) compounds have been shown to induce apoptosis in a number of human leukemia cell lines of different haematological lineage, suggesting their potential as anti-cancer agents. In this study, we sought to determine if PBOX-6, a well characterised member of the PBOX series of compounds, is also an effective inhibitor of breast cancer growth. Two estrogen receptor (ER)-positive (MCF-7 and T-47-D) and two ER-negative (MDA-MB-231 and SK-BR-3) cell lines were examined. The 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to determine reduction in cell viability. PBOX-6 reduced the cell viability of all four cell lines tested, regardless of ER status, with IC(50) values ranging from 1.0 to 2.3 microM. PBOX-6 was most effective in the SK-BR-3 cells, which express high endogenous levels of the HER-2 oncogene. Overexpression of the HER-2 oncogene has been associated with aggressive disease and resistance to chemotherapy. The mechanism of PBOX-6-induced cell death was due to apoptosis, as indicated by the increased proportion of cells in the pre-G1 peak and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, intratumoural administration of PBOX-6 (7.5 mg/kg) significantly inhibited tumour growth in vivo in a mouse mammary carcinoma model (p=0.04, n=5, Student's t-test). Thus, PBOX-6 could be a promising anti-cancer agent for both hormone-dependent and -independent breast cancers.
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PMID:The pyrrolo-1,5-benzoxazepine, PBOX-6, inhibits the growth of breast cancer cells in vitro independent of estrogen receptor status and inhibits breast tumour growth in vivo. 1621 9

Given the important prognostic and predictive utility of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2) [human epidermal growth factor receptor-2 (HER2/neu)] in breast cancer, it is recommended that ErbB2 testing be performed on all invasive breast cancers at the time of diagnosis. A consensus, however, has not yet been reached as to the optimal method of evaluating ErbB2 status. Immunohistochemistry to detect protein overexpression and fluorescence in situ hybridization (FISH) to detect ErbB2 gene amplification are the most frequently used methods. As no one detection method fulfills all necessary requirements of reliability, reproducibility, and ease of use, we developed a novel approach in the form of a simple assay we refer to as protein and gene double staining (PGDS) which simultaneously evaluates protein overexpression and gene amplification by combining immunohistochemistry with chromogenic in situ hybridization (CISH). A total of 134 invasive breast carcinomas, including 81 cases with a full-face section and 53 cases included in a tissue microarray (TMA), were assessed by PGDS, and the results were correlated with ErbB2 gene amplification status as determined by FISH. ErbB2 gene copy number determined by CISH analysis in the PGDS assay showed excellent concordance with that of FISH (correlation coefficient 0.82; P<0.001 with full-face section cases, and 0.98; P<0.001 with cases in a TMA). The overall concordance rate for gene amplification status between PGDS and FISH was 90.12% in cases with a full-face section and 92.45% with TMA cases. Perfect correlation was seen between the PGDS assay and FISH in cases that were considered either nonamplified or highly amplified by the dual assay. Of the 17 cases that showed low amplification by PGDS, 5 were classified as nonamplified by FISH. Correction for chromosome 17 copy number in the FISH assessment contributed to the discordance between CISH and FISH results. This newly developed PGDS method represents a novel approach to ErbB2 status determination that combines the assessment of both protein overexpression and gene amplification in one simple assay. It is likely that this assay will aid in immunohistochemical calibration and will also increase the sensitivity and specificity of ErbB2 testing.
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PMID:PGDS, a novel technique combining chromogenic in situ hybridization and immunohistochemistry for the assessment of ErbB2 (HER2/neu) status in breast cancer. 1772 Dec 78

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called "curry powder") that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an "old-age" disease such as cancer requires an "age-old" treatment.
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PMID:Curcumin and cancer: an "old-age" disease with an "age-old" solution. 1846 66

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. In this study, we have demonstrated that treatment of different human breast cancer cell lines with honokiol resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines. The inhibition of growth was associated with a G1-phase cell cycle arrest and induction of caspase-dependent apoptosis. The effects of honokiol might be reversely related to the expression level of human epidermal growth receptor 2, (HER-2, also known as erbB2, c-erbB2) since knockdown of her-2 expression by siRNA significantly enhanced the sensitivity of the her-2 over-expressed BT-474 cells to the honokiol-induced apoptosis. Furthermore, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in her-2 over-expressed breast cancer cells. Finally, we showed that honokiol was able to attenuate the PI3K/Akt/mTOR (Phosphoinositide 3-kinases/Akt/mammalian target of rapamycin) signalling by down-regulation of Akt phosphorylation and upregulation of PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) expression. Combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on induction of apoptosis of breast cancer cells. In conclusion, honokiol, either alone or in combination with other therapeutics, could serve as a new, promising approach for breast cancer treatment.
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PMID:Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer. 1858 72

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ERalpha), progesterone receptor B, NF-kappaB, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ERalpha, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.
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PMID:Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells. 1876 37

PURPOSE We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase IIalpha (Topo-IIalpha) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-IIalpha copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-IIalpha and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541. PATIENTS AND METHODS Topo-IIalpha and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-IIalpha, HER2, and chromosome 17 (CEP17). Topo-IIalpha and/or HER2 were classified as amplified (> or = two copies/CEP17, deleted (< or = 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results Topo-IIalpha/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-IIalpha was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-IIalpha amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-IIalpha was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted tumors (17 of 69; 25%). Although Topo-IIalpha-amplified tumors were nearly always HER2 amplified, these tumors did not receive benefit from increasing the dose of CAF (P = .15). CONCLUSION The correlative companion study CALGB 8541-150013 does not support the hypothesis that Topo-IIalpha amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer.
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PMID:Topoisomerase II{alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER2-amplified early breast cancer: results of CALGB 8541/150013. 1947 Sep 42


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