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At least 415 records · Page 23Linked to original sources
PubMed2006

EGFR-targeted therapy and related skin toxicity.

OBJECTIVES: To discuss the mechanism by which epidermal growth factor receptor (EGFR)-targeted agents work, the resulting cutaneous toxicities, the pathophysiology of the unique rash associated with these agents, and the management of these skin problems. DATA SOURCES: Published scientific papers, review articles, book chapters, and clinical experiences. CONCLUSION: These new targeted agents result in unique cutaneous toxicities. Researchers and clinicians have made numerous suggestions for managing the various side effects, although there is currently no research to guide evidence-based practice. IMPLICATIONS FOR NURSING PRACTICE: With any new treatment option, it is imperative that nurses understand how agents work to enrich their own knowledge base, as well as have a strong foundation for patient education. It is important that nurses understand potential side effects of these agents, know of possible interventions, and participate in research to identify effective interventions.

Antibodies, Monoclonal↗
PubMed2000

Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system.

Epstein-Barr virus (EBV) targeted therapeutic strategies for viral associated malignant diseases have received only perfunctory consideration, first, because latent herpesviruses have been intractable to antiviral chemotherapy and, second, because the role EBV has in maintenance of the malignant cell phenotype has been uncertain. Two patients with EBV related primary central nervous system lymphoma (PCNSL) in the setting of advanced AIDS, were treated with low dose hydroxyurea based on in vitro anti-EBV activity. The responses obtained here suggest the promise of antiviral approaches in select cancers.

Adolescent↗
PubMed2004

Targeted therapies in myelodysplastic syndromes: ASH 2003 review.

The myelodysplastic syndromes (MDS) continue to pose conceptual and practical conundrums because of their heterogeneity and therapeutic challenges. They are not restricted to the presence of clonal cells that are prone to excessive proliferation and premature apoptosis. In MDS the bone marrow microenvironment also is abnormal and exhibits an excess of proinflammatory cytokines, especially tumor necrosis factor (TNF), neoangiogenesis, and poorly defined immune defects. Thalidomide, a drug with anti-TNF, antiangiogenic, and immunomodulatory activities, and other agents with anti-TNF effects, such as pentoxifylline, etanercept, and infliximab, have produced hematologic improvement in 20% to 40% of patients. These agents may provide effective therapy for a subset of lower-risk MDS patients, even if the drugs target the bone marrow microenvironment predominantly. However, in higher-risk MDS patients, especially those with more than 10% blasts, it is important to eliminate abnormal cell clones; drugs used for this purpose have included arsenic trioxide, topotecan, the farnesyl transferase inhibitor tipifarnib, and demethylating agents, such as 5-azacytidine and decitabine. To increase the therapeutic index, a combination strategy may be preferable for higher-risk MDS patients, in whom the seed (clone) and the soil (bone marrow microenvironment) must be targeted simultaneously. The challenge is to recognize the subset that is likely to respond to a given drug so that patients can be preselected for therapy.

Animals↗
PubMed2006

[Gastrointestinal stromal tumors (GIST)--a paradigm of successful targeted therapy of solid tumors].

Gastrointestinal stromal tumors (GIST) have attracted basic scientists as well as clinicians in the last 10 years. The reason for this is explanation of the pathogenetic mechanism of tumor growth by activation of c-Kit protein, followed by a rationally designed suppressor, a drug named imatinib. It is the first successful therapy for solid tumors to date, although there are other ongoing studies of agents with targeted action on different molecules in different tumors. In 80% of patients there is a clinical benefit from imatinib trreatment. GIST shows great diversity in clinical presentation and some questions still remain, such as malignant potential and prognostic criteria in these tumors. Imatinib therapy demonstrates many favorable effects such as acceptable toxicity and relative mild side effects, excellent quality of life, good patient compliance, etc. There are ongoing trials of new agents designated for target molecules, which would hopefully show benefit after developing resistance to imatinib.

Antineoplastic Agents↗
PubMed2002

Emerging cancer-targeted therapies.

There is reason to believe that the unfolding revolution in molecular biology and translational research will allow selective targeting of tumor cells, and radically change the way general practitioners and pediatric oncologists treat and follow children with cancer. This article highlights some of the most promising approaches being tested in the field. By learning about the underlying biology, the remaining hurdles, the projected timeline, and the possible impact of new therapies on the practice of pediatric oncology, health care professionals and patients should be better prepared for the future of pediatric oncology.

Cancer Vaccines↗
PubMed1998

Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA.

Telomerase is the RNA-protein complex which elongates telomeric DNA (TTAGGG)n and appears to play an important role in cellular immortalization. The almost exclusive expression of telomerase in tumor cells, and not in most normal cells, offers an exciting opportunity for therapy by inhibiting its function. Here, we have investigated the effect of inhibition of telomerase on the growth and survival of human malignant glioma cells in vitro and in vivo by using a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A). 2-5A antisense functions by activating the endoribonuclease, RNase L, resulting in the degradation of single stranded, targeted RNA. We have shown that the 2-5A antisense treatment effectively suppressed tumor cell growth and survival in vitro. Furthermore, treatment of tumors grown in nude mice with the antisense oligonucleotide inhibited survival of the tumor cells. TUNEL assays suggest that this effect is mediated through the induction of apoptosis. Targeting telomerase RNA with 2-5A antisense, therefore, may represent an effective and novel approach for treatment of a broad range of cancers.

Animals↗
PubMed2005

Erlotinib: small-molecule targeted therapy in the treatment of non-small-cell lung cancer.

BACKGROUND: Erlotinib is an oral tyrosine kinase inhibitor, targeting the human epidermal receptor type 1/ epidermal growth factor receptor, recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) after the failure of more than 1 or 2 previous chemotherapeutic regimens. OBJECTIVE: The purpose of this article is to summarize the development, pharmacology, pharmacokinetics, efficacy, and adverse effects of erlotinib. METHODS: A literature search was conducted with the MEDLINE and EMBASE (1999-2005) databases using the search terms non-small-cell lung cancer, erlotinib, and epidermal growth factor receptor inhibitor. Abstracts from the American Society of Clinical Oncology and documents submitted to the FDA also were reviewed. RESULTS: BR.21, a randomized, placebo-controlled, multinational Phase III trial demonstrated clinically and statistically improved overall survival in patients with advanced or metastatic NSCLC treated with erlotinib versus placebo as second-line therapy. The erlotinib group had a median survival of 6.7 months versus a median survival of 4.7 months in the placebo group (P < 0.001). The toxicity profile of erlotinib was moderately benign, with the most commonly documented adverse events requiring dose reductions including skin rash (12%) and diarrhea (5%). Interstitial lung disease and relative fatalities were reported infrequently (0.8%) in patients receiving erlotinib. Two randomized, placebo-controlled, multicenter Phase III trials conducted in patients with locally advanced and metastatic NSCLC showed no clinical benefit with first-line administration of erlotinib plus concurrent platinum-based chemotherapy. CONCLUSIONS: For patients with NSCLC in whom more than 1 or 2 previous chemotherapeutic regimens have failed, erlotinib is an effective therapy with significant overall survival benefits. The use of erlotinib as first-line therapy in combination with platinum-based chemotherapeutic regimens, however, has failed to demonstrate efficacy in the treatment of NSCLC.

Administration, Oral↗
PubMed1999

Antibody-targeted therapy for low-grade lymphoma.

Monoclonal antibodies (MoAbs) have now become a successful treatment for selected patients with non-Hodgkin's lymphoma (NHL). Antibody targets most commonly used for the treatment of B-cell NHL include CD20, CD19, and CD22. Unconjugated MoAbs are cytotoxic by several mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and signal transduction leading to apoptosis. In an attempt to augment the effectiveness of naked antibody preparations, various radioconjugates, immunotoxins, chemotherapeutic agents, or immune-modifiers have been attached to the antibodies. The immunotoxin tested most extensively in clinical trials is B4-blocked ricin (anti-CD19 with a partially blocked ricin toxin). The use of radioimmunoconjugates to augment the effectiveness of unlabeled antibodies has been one of the most popular strategies. Antibodies against these targets have now been chelated with radioconjugates such as 131I or 90Y and tested in recent clinical trials. Radioimmunotherapy has the theoretical advantage over naked antibody therapy or immunotoxin therapy in that the MoAb conjugated with a radioisotope can have a "cross-fire" effect such that antigen-negative tumor cells adjacent to those expressing the target antigen may also be killed. This may enhance the likelihood of tumor sterilization even in fairly bulky disease. Future studies will focus on testing these antibodies in larger patient populations, sequentially or in combination, and on combining MoAb therapy with standard- or high-dose chemotherapy and hematopoietic stem-cell transplantation.

Antibodies, Anti-Idiotypic↗
PubMed2006

Anti-CD45 monoclonal antibody YAML568: A promising radioimmunoconjugate for targeted therapy of acute leukemia.

UNLABELLED: The outcome of hematopoietic cell transplantation for hematologic malignancies may be improved by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the biodistribution of 111In-labeled anti-CD45 antibody in humans using the rat IgG2a monoclonal antibody YAML568 that recognizes a common CD45 epitope present on all human leukocytes. METHODS: Eight patients undergoing bone marrow transplantation received YAML568 labeled with 122 +/- 16 MBq of 111In intravenously followed by serial blood sampling, urine collection, and conjugated view planar gamma-camera imaging up to 144 h after injection. Time-activity curves were obtained using region-of-interest analysis in the accumulating organs and residence times were calculated. An estimate for the radiation-absorbed doses for each organ per unit of administered activity of 90Y was calculated using software for internal dose assessment. The first patient received no unlabeled antibody preloading. The second 2 patients received a preloading dose of 10 mg (0.15 mg/kg). The last 5 patients received a preloading dose of 30-47 mg (0.5 mg/kg). RESULTS: No significant administration-related side effects were seen. The 3 patients receiving no antibody or low antibody preloading had an unfavorable biodistribution with a high initial accumulation of activity in the liver (37%) and the spleen (34%). For the patients receiving 0.5-mg/kg antibody preloading, the estimated radiation-absorbed doses for red bone marrow, spleen, liver, kidney, and total body were 6.4 +/- 1.2, 19 +/- 5, 3.9 +/- 1.4, 1.1 +/- 0.4, and 0.6 +/- 0.1 mGy/MBq, respectively, demonstrating preferential red marrow targeting. A linear regression model showed that the amount of unlabeled antibody preloading per body weight has a strong influence on the estimated red marrow absorbed dose (P = 0.003, R2 = 0.80). CONCLUSION: This study shows that the anti-CD45 monoclonal antibody YAML568 is suitable for delivering selectively radiation to hematopoietic tissues when labeled with 90Y provided that a preloading dose of about 0.5 mg/kg unlabeled antibody is given.

Adult↗
PubMed2006

[Requirements for the development of molecularly defined targeted therapy in oncology].

BACKGROUND: The revolutionary development in the biosciences during the last 15 years--including the sequencing of the human genome and multiple other genomes as well the possibility of massive parallel analysis of thousands of data points within a single experiment--have greatly improved our understanding of the pathophysiology of tumor development and progression as well as metastasis. THE CURRENT SITUATION: The further development of genomic technology for routine clinical use is slowly but steadily leading to a paradigm shift: the currently used tumor definition based on pathologic and histological assessment is replaced by molecularly defined tumor subtypes. This is an essential prerequisite for the development of molecularly defined individualized therapies in oncology leading to more effective treatments with less severe side effects. The first molecularly defined drugs (targeted drugs) have already entered the clinical arena. However, not only diagnostics and therapy on oncology will change dramatically in the future, but also the way we have to organize oncology itself. OUTLOOK: The integration of genomics and information technologies will require the establishment of interdisciplinary teams beyond the already established collaborations between surgeons, radiotherapists and medical oncologists.

Algorithms↗
PubMed1999

Utilization of variant-type of human alpha-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma.

We previously reported that the retroviral vector (LNAFW0.3TK) expressing the herpes simplex thymidine kinase (HSVtk) gene under the control of the 0.3 kb human alpha-fetoprotein (AFP) promoter provided the ganciclovir (GCV)-mediated cytotoxicity in the high AFP-producing (HuH-7) but not in the low AFP-producing (huH-1/cl.2) human hepatoma cells. In the present study, we constructed the retroviral vector (LNAFM0.3TK) in which the HSVtk gene expression is regulated by the variant-type of the 0.3 kb human AFP promoter with a G-to-A substitution at nucleotide -119, a point mutation responsible for hereditary persistence of human AFP and the vector was applied to three human hepatoma cell lines HuH-7, huH-1/cl.2 and intermediate AFP-producing cells (PLC/PRF/5). By the reporter gene transfection assay, the activity of the variant-type of the promoter was much higher than that of the wild-type of the promoter in both HuH-7 and huH-1/cl.2 cells. Consistent with this, LNAFM0.3TK infection could sensitize huH-1/cl.2 cells, as well as HuH-7 and PLC/PRF/5 cells to GCV, but did not affect cell growth of nonhepatoma cells (HeLa). In addition, the bystander effect was achieved more efficiently by LNAFM0.3TK infection than LNAFW0.3TK infection in HuH-7 cells. These results suggest that the variant-type of the human AFP promoter ensures the therapeutic gene expression in gene therapy particularly for the low AFP-producing hepatoma cells.

Carcinoma, Hepatocellular↗
PubMed1995

Antihypertensive therapy targeted to the needs of the patient: focus on the renin-angiotensin system; older and newer agents.

Antihypertensive drug therapy can lower blood pressure and prolong life, but many hypertensive patients continue to develop further risk factors and to die prematurely of heart disease. Antihypertensive drugs can also interfere with the patient's quality of life, and many are not compatible with the concomitant medical conditions of the patient and the medications taken to treat them. For these reasons, the antihypertensive therapy selected should meet the specific and complete needs of each patient, not just treat the high blood pressure. An analysis of the drugs that inhibit the renin-angiotensin system suggests that several of these drugs have a more favorable therapeutic profile than other classes of hypotensive agents. The newly developed receptor-site-specific blockers are expected to be tolerated better by hypertensive patients and, consequently, to enhance their quality of life. The first of the new class of nonpeptide blockers of the AT1 receptor, losartan--which has no partial agonist activity--is likely to have the advantages of the angiotensin-converting enzyme inhibitors without their adverse effects, notably cough. In selected patients, the AT1-receptor blockers could become the drugs of first choice for the management of hypertension.

Angiotensin II↗
PubMed2005

Evolving molecular-based targeted therapy for cancer: an exciting field.

The development of molecular biology tools has led to the identification of numerous therapeutic targets in cancer cells. In this article, we discuss the rational and clinical data supporting the use of agents that selectively target epidermal and vascular endothelial growth factors in selected cancers.

Antibodies, Monoclonal↗
PubMed2004

[Novel angiogenesis inhibitors for molecular target therapy of cancer].

Angiogenesis, neovascularization from pre-existing vasculature, is essential to allow growth of primary solid tumors and to enable metastasis. Recent biological studies in both tumor and endothelial cells have begun to present a wide variety of molecular targets for developing angiogenesis inhibitors. Therefore, angiogenesis inhibitors including anti-angiogenic agents as well as anti-vascular targeting agents have become promising drugs in cancer chemotherapy. However current unsolved problems in anti-angiogenic therapy are the lack of surrogate markers for therapeutic efficacy, as well as of establishment of effective combinations with other therapeutic approaches including conventional anticancer therapy, radiotherapy, and immunotherapy. This article focuses on the promising drugs with anti-angiogenic activity and their molecular targets under clinical trials, as well as the significance of clinical evaluation for anti-angiogenic therapies.

Angiogenesis Inhibitors↗
PubMed2006

Targeted therapies in combination with chemotherapy in non-small cell lung cancer.

With rare exceptions, attempts to combine so-called targeted agents with standard cytotoxic chemotherapy in advanced non-small cell lung cancer have yielded disappointing results. The reasons underlying these spectacular failures are not always fully understood, but certainly the lack of careful patient selection is a major contributing factor. In addition, recent preclinical and clinical studies indicate that antagonism may exist between the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy primarily in tumor cells with wild-type EGFR. By contrast, tumor cells harboring somatic mutations in EGFR experience massive apoptosis when exposed to the EGFR tyrosine kinase inhibitors. Therefore, in theory, mutant tumor cells should exhibit enhanced cell kill when treated with concomitant chemotherapy and EGFR tyrosine kinase inhibitors akin to what is observed with chemotherapy and trastuzumab in breast cancer. Clinical data from the recently completed TRIBUTE trial support the latter possibility. Ideally, future studies of EGFR tyrosine kinase inhibitors and other targeted drugs will use careful patient selection criteria based on well-characterized and validated predictive markers. However, in the absence of such biomarkers, clinical judgment, common sense, and innovative clinical trial design are necessary to avoid undue delay in drug development.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Towards the targeted therapy of melanoma.

Novel anti-cancer treatments use knowledge about the underlying biology of the tumor to find suitable molecular targets. The recent years have seen great advances in understanding the biology of melanoma. In the current review we discuss the most promising molecular targets for melanoma and suggest possible strategies for overcoming resistance.

Antineoplastic Agents↗