[Targeting therapy for malignant brain tumors].
Explore the source record for details and available documents.
Antineoplastic Agents↗
SEARCH · Search PubMed
Results for “Targeted Therapy”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
[Expectation of new antituberculous drugs and targeting therapy for treatment of mycobacterial infections].
Recent AIDS endemic causes the worldwide increase in intractable mycobacterial infections including extrapulmonary tuberculosis due to drug resistant organisms and disseminated Mycobacterium avium complex infections. Therefore, new antituberculous (antimycobacterial) drugs and development of regimens and protocols for clinical treatment of such mycobacterial infections are urgently needed. Here, I described the present situations of new antituberculous agents, in particular new rifamycin derivatives including rifabutin and benzoxazinorifamycin (KRM-1648), new macrolides such as clarithromycin and azithromycin, and new quinolones including sparfloxacin, ofloxacin, ciprofloxacin, fleroxacin, AM-1155 and so on. Their in vitro antimycobacterial activities, therapeutic efficacy against experimental infections induced in animals especially in mice, and clinical trials using these drugs are summarized by referring to recent studies by worldwide investigators including us. Moreover, this paper dealt with some of recent attempts for chemotherapy of mycobacterial infections employing the drug delivery system using liposomal microvesicles as a carrier of drugs. Although these new drugs and development in new regimens appreciably potentiated the efficacy of controlling mycobacterial infections, in particular M. avium complex infections, it remains very difficult to achieve a complete elimination of the organisms from the sites of infection, even if provided multi-drug regimens using new drugs having excellent antimycobacterial activity and sufficient dosages. Therefore, it seems important to make an effort to elucidate the mechanisms of induction of immuno-unresponsiveness in hosts in progressed state of mycobacterial infection, as well as to develop new drugs possessing more potent antimycobacterial activity.
Animals↗
TCR alpha/beta targeted therapy in the rat: pretreatment with R73 monoclonal antibody induces profound immunological anergy and long-term allograft survival.
Explore the source record for details and available documents.
Animals↗
[Two cases of long-term survival with hepatocellular carcinoma following targeting therapy with SMANCS/lipiodol].
We performed arterial infusion of SMANCS/Lipiodol in nineteen cases with hepatocellular carcinoma (HCC). We report two of these cases who survived for more than five years after the initial treatment. In case 1, HCC responded very well to the initial subsegmental infusion of SMANCS/Lipiodol with a prominent decrease in AFP level. In case 2, a 63-year-old male, repeated subsegmental infusion of SMANCS/Lipiodol for the local recurrence controlled the tumor well. In both cases, an approximately three-year period of complete remission passed until the tumor recurred. Arterial infusion of SMANCS/Lipiodol is expected to be a potent treatment for HCC. Its administration should be subsegmental, if possible, and should be repeated for local recurrence with a careful follow-up study.
Aged↗
Systemic sclerosis: current pathogenetic concepts and future prospects for targeted therapy.
Although there is no cure for systemic sclerosis, the disease is certainly treatable. And the more that is understood of its pathogenesis, the better the prospects for treatment. Excessive collagen deposition in the skin and viscera is responsible for the morbidity and mortality. The immune system plays a critical role in setting up the fibrotic process, but impaired regulation of collagen gene expression probably underlies the persistence of fibrosis. The development of effective antifibrotic drugs, in particular agents that inhibit transcription factors involved in the activation of type I collagen genes, is likely to be the way forward for treatment of the later stages of diffuse systemic sclerosis, with immunomodulatory therapy for the earlier stages.
Collagen↗
[Diagnosis and targeting therapy of colorectal cancer using antibody].
Application of monoclonal antibody for diagnosis and therapy of colorectal cancer was reviewed. The history and present status of radioimmunoimaging of cancer were presented. Immuno-guided surgery using radiolabeled antibody and hand-aided detector during surgery is a promising approach for complete excision of cancerous region. Also, a new antibody labeling method using a micro-magnet instead of radioisotopes may lead to a new era in immunodiagnosis of cancer. Finally, immunotargeting chemotherapy using antibody-anticancer drug conjugates was reviewed. A new type of immunoconjugate composed of human/mouse chimeric antibody and Neocarzinostatin seems to be one of the most promising drug formulas for immunotargeting chemotherapy.
Antibiotics, Antineoplastic↗
[Experimental study on targeting therapy of human hepatocellular carcinoma in nude mice using adriamycin-anti-transferrin receptor conjugate].
Conjugate between adriamycin and anti-transferrin receptor monoclonal antobody WuT9 was prepared with Dextran T10 as a bridge, and it was proved to retain both the drug cytotoxity and antibody activity. The conjugate or its individual components were administered to athymic mice bearing SMMC-7721 human hepato-cellular carcinoma (HCC) cells. These agents were given 2, 5, 8 days after inoculation of tumor cells (1 x 10(7) per mouse). Tumor size was measured daily (geometric mean diameter, GMD) and latent period recorded. All the animals were killed on day 35 to measure tumor weight and natural killer (NK) activity of splenic lymphocytes. The results showed that the latent period in the conjugate treated group was much longer than that in Adr treated group (33.0 days vs 25.0 days), and that GMD on day 35 in the conjugate treated group was much smaller than that in Adr treated group (3.80 +/- 1.9 mm vs 6.69 +/- 2.3 mm, P < 0.05). In addition, NK activity in the conjugate treated group was higher than that in Adr treated group (28.2 +/- 8.2% vs 15.1 +/- 3.6%, P < 0.05). The results suggest that adriamycin-anti-transferrin receptor conjugate might be useful in the treatment of human HCC.
Animals↗
Enzymatic activation of prodrugs by prostate-specific antigen: targeted therapy for metastatic prostate cancer.
Explore the source record for details and available documents.
Animals↗
Superantigen-targeted therapy: phase I escalating repeat dose trial of the fusion protein PNU-214565 in patients with advanced gastrointestinal malignancies.
Antibody-directed, superantigen-induced cytotoxicity has been shown to have potent in vitro and in vivo antitumor effects in preclinical models. In the present study, PNU-214565, a recombinant fusion protein consisting of the Fab of the monoclonal antibody C242 and staphylococcal enterotoxin A (SEA), was used in an escalating repeat dose Phase I clinical trial in patients with advanced gastrointestinal malignancies. A prior single-dose Phase I clinical trial had demonstrated safety at doses of 1.5 ng/kg with toxicities of fever and hypotension that were not dose related. Twenty-seven patients (age range, 36-75 years; median, 62; 14 males and 13 females; 23 colorectal and 4 pancreatic) were treated in the present study with one cycle of four consecutive daily 3-h infusions of PNU-214565 at doses of 0.15 ng/kg (n = 3); 0.5 ng/kg (n = 3), 1.5 ng/kg (n = 4), 2.75 ng/kg (n = 12), and 3.5 ng/kg (n = 5). All patients had a good performance status [Eastern Cooperative Oncology Group: PS = 0 (n = 15), PS = 1 (n = 12)]. As in the single-dose trial, fever and hypotension were the most common toxicities. Dose-limiting toxicity (DLT), consisting of transient hypotension responsive to dopamine, was experienced by one patient treated at the 2.75 ng/kg dose level. One patient with pancreatic cancer metastatic to the liver experienced a partial response of hepatic metastases with stable pancreatic head abnormalities by computed tomography scan. Further dose escalation was suspended when two patients treated in a companion repeat dose Phase I study experienced DLT at the 4 ng/kg dose level. Multiparameter analyses on all patients treated in the two companion single-dose and two-repeated-dose Phase I trials revealed that the levels of patients' pretreatment anti-SEA antibodies protected against toxicity at a given drug dose. By jointly considering weight and the baseline anti-SEA concentration in a patient, it is possible to assign a PNU-214565 dose that will induce systemic cytokine release (a surrogate test to assess for the presence of uncomplexed drug and its ability to induce systemic cellular activation) without DLT. This pharmacodynamically based dosing scheme will be tested in future repeated-dose clinical trials and will define maximally tolerated doses of this powerful new immunotherapy approach.
Adult↗
Gefitinib (Iressa, ZD1839) and tyrosine kinase inhibitors: the wave of the future in cancer therapy.
Targeted therapies are one of the latest innovative trends in cancer therapy. The epidermal growth factor receptor (EGFR) is a target found in high concentrations in several solid tumors including lung, breast, colorectal, and brain. Tyrosine kinase inhibitors, such as gefitinib (Iressa, ZD1839), block the EGFR. As a result, there is inhibition of cellular proliferation, promotion of apoptosis, and inhibition of anti-angiogenesis. Gefitinib has demonstrated significant efficacy in non-small-cell lung cancer (NSCLC), leading to FDA approval for treatment of this refractory disease. Phase 2 trials with gefitinib for platinum refractory NSCLC reported disease response and symptom improvement. Early results of phase 2 studies of gefitinib, combined with standard chemotherapy in colorectal cancer, showed a 75% response rate compared with 55% with standard therapy alone. Gefitinib, combined with flutamide, produced an additive growth inhibition in prostate cancer. A phase 2 trial of gefitinib in first-relapse glioblastoma multiforme demonstrated median overall survival from treatment start of 39.4 weeks compared with 40 weeks with standard chemotherapy. Gefitinib is an oral agent with a mild toxicity profile, and thus, may be an optimal addition to chemotherapeutic regimens for some solid tumors. Gefitinib is potentially a vital and useful weapon in the arsenal of cancer therapies.
Administration, Oral↗
Trisomy 8 in Philadelphia-negative cells during imatinib therapy.
Targeted therapy with imatinib selectively suppresses Philadelphia-positive cells in chronic myeloid leukemia cells, with reappearance of apparently normal hemopoiesis in a considerable number of patients. Recently, clonal abnormalities have been observed in Philadelphia-negative cells during imatinib therapy, the biologic and prognostic significance of which is actually unknown. A case of trisomy 8 occurring in Philadelphia-negative cells, which was treated by bone marrow transplantation, is reported. Chromosomal abnormalities in Philadelphia-negative cells do not seem to herald disease transformation, but the long-term prognosis may be influenced by an increased incidence of myelodysplasia in younger patients.
Benzamides↗
Recombinant immunotoxins in targeted cancer cell therapy.
Targeted cancer therapy in general and immunotherapy in particular combines rational drug design with the progress in understanding cancer biology. This approach takes advantage of our recent knowledge of the mechanisms by which normal cells are transformed into cancer cells, thus using the special properties of cancer cells to device novel therapeutic strategies. Recombinant immunotoxins are excellent examples of such processes, combining the knowledge of antigen expression by cancer cells with the enormous developments in recombinant DNA technology and antibody engineering. Recombinant immunotoxins are composed of a very potent protein toxin fused to a targeting moiety such as a recombinant antibody fragment or growth factor. These molecules bind to surface antigens specific for cancer cells and kill the target cells by catalytic inhibition of protein synthesis. Recombinant immunotoxins are developed for solid tumors and hematological malignancies and have been characterized intensively for their biological activity in vitro on cultured tumor cell lines as well as in vivo in animal models of human tumor xenografts. The excellent in vitro and in vivo activities of recombinant immunotoxins have lead to their preclinical development and to the initiation of clinical trail protocols. Recent trail results have demonstrated potent clinical efficacy in patients with malignant diseases that are refractory to traditional modalities of cancer treatment: surgery, radiation therapy, and chemotherapy. The results demonstrate that such strategies can be developed into a separate modality of cancer treatment with the basic rationale of specifically targeting cancer cells on the basis of their unique surface markers. Efforts are now being made to improve the current molecules and to develop new agents with better clinical efficacy. This can be achieved by development of novel targeting moieties with improved specificity that will reduce toxicity to normal tissues. In this review, the design, construction, characterization, and applications of recombinant immunotoxins are described. Results of recent clinical trails are presented, and future directions for development of recombinant immunotoxins as a new modality for cancer treatment are discussed.
Clinical Trials as Topic↗
Deciphering mitochondrial metabolic vulnerabilities in ovarian clear cell carcinoma with mass spectrometry-based clinical proteomics.
INTRODUCTION: Ovarian clear cell carcinoma (OCCC) is a rare gynecologic malignancy with a high mortality rate and a lack of response to standard chemotherapy. Despite the functional association between the loss of ARID1A and mitochondrial dependency, the clinical translation of mitochondria-targeted therapies in OCCC has been hindered by a substantial disconnect between biological insight and therapeutic application. There is an urgent, unmet need to identify novel, more specific and effective therapies targeting the mitochondria-related molecular vulnerabilities of ARID1A-mutant OCCC. AREAS COVERED: This critical perspective is informed by results from PubMed literature searches and recent webinars and presentations providing insight into opportunities for mass spectrometry (MS)-based proteomic approaches to enhance and accelerate the clinical translation of mitochondria-targeted therapies in OCCC. EXPERT OPINION: The MS-based proteomic analysis of clinically-relevant experimental models of OCCC will provide a unique opportunity to progress beyond simplified preclinical models and incorporate the full spectrum of patient-specific systemic and microenvironmental factors that may influence therapeutic response, including the adipocyte-related metabolic dependencies of OCCC. Targeted MS is a precise and robust approach that can be applied to verify these novel, mechanistic insights into how mitochondria-targeted therapies intersect with tumor metabolism in OCCC.
Humans↗
Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy.
Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.
Animals↗
Dynamics and control of Schistosoma haematobium transmission in Kenya: an overview of the Msambweni Project.
Ecologic modeling of Schistosoma transmission in endemic communities has suggested that antiparasite therapy targeted at the most heavily infected segment of the human population (i.e., school-age children) should have a significant impact on local parasite transmission. Our 1984-1991 experience with age-targeted therapy in the Msambweni area of Kenya has shown an overall decrease in area transmission within 1-2 years following initiation of annual treatment of school-age groups. Snail monitoring confirmed a continuing but variable reduction of vector infection rates. However, subgroup analysis showed significant differences in transmission suppression between more developed coastal villages with piped-water kiosks and villages with only limited access to safe water supplies. Villages without piped water were marked by higher initial prevalences of S. haematobium infection, greater prevalence among adults, longer and more frequent contact with high-risk water sources, and persistently high transmission despite compliance with parasitologic screening or drug therapy. We conclude that targeted therapy had a significant impact on S. haematobium transmission in some areas, but that more extensive or more prolonged coverage is necessary to reduce the rate of new infection in high-risk villages. Defining field-use algorithms, based on decision analysis of economic and ecologic parameters, should provide effective guidelines for selective versus mass treatment in expanded control areas.
Adolescent↗
New treatment strategies for malignant gliomas.
Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma multiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Several low molecular weight signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials. The efficacy of these agents as monotherapies has been modest, at best; however, small subsets of patients who harbor specific genetic changes in their tumors may display favorable clinical responses to defined small molecule inhibitors. Multitargeted kinase inhibitors or combinations of agents targeting different mitogenic pathways may overcome the resistance of tumors to single-agent targeted therapies. Well designed studies of small molecule kinase inhibitors will include assessment of safety, drug delivery, target inhibition and correlative biomarkers to define mechanisms of response or resistance to these agents. Predictive biomarkers will enrich for patients most likely to respond in future clinical trials. Additional clinical studies will combine novel targeted therapies with radiation, chemotherapies and immunotherapies.
Antineoplastic Agents↗
A3 adenosine receptor as a target for cancer therapy.
Targeting the A3 adenosine receptor (A3AR) by adenosine or a synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) results in a differential effect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor cell types such as melanoma, colon or prostate carcinoma and lymphoma. This effect is specific and is exerted on tumor cells only. Moreover, exposure of peripheral blood mononuclear cells to adenosine or the agonists leads to the induction of granulocyte colony stimulating factor (G-CSF) production. When given orally to mice, the agonists suppress the growth of melanoma, colon and prostate carcinoma in these animals, while inducing a myeloprotective effect via the induction of G-CSF production. The de-regulation of the Wnt signaling pathway was found to be involved in the anticancer effect. Receptor activation induces inhibition of adenylyl cyclase with a subsequent decrease in the level of protein kinase A and protein kinase B/Akt leading to activation of glycogen synthase kinase-3beta, a key element in the Wnt pathway. The oral bioavailability of the synthetic A3AR agonists, and their induced systemic anticancer and myeloprotective effect, renders them potentially useful in three different modes of treatment: as a stand-alone anticancer treatment, in combination with chemotherapy to enhance its therapeutic index and myelprotection. It is evident that use of the A3AR agonist for increasing the therapeutic index of chemotherapy may also invariably give rise to myeloprotection and vice versa. The A3AR agonists are thus a promising new class of agents for cancer therapy.
Adenosine↗
T cell targeting in cancer therapy.
Targeting of immune cells by bispecific antibodies has proven a powerful tool for the investigation of cellular cytotoxicity, lymphocyte activation and induction of cytokine production, as well as to represent an innovative form of immunotherapy for the treatment of cancer. The hallmark of this approach is the use of the specificity of monoclonal antibodies to join target and immune cells by virtue of the dual specificity of bispecific antibodies for the two entities. More precisely the bispecific antibody has two different binding sites, which are capable of recognizing tumor associated antigens on the one hand and lymphocyte activation sites on the other. This process of crosslinking results in the activation of the lymphocyte and triggering of its lytic machinery, as well as lymphokine production. A major advantage of this therapeutic modality is, that use is made of the normal cellular immune defence system and therefore is only associated with minor toxicity. The distinct lymphocyte populations, which can be used for adoptive immunotherapy and the various bispecific antibody preparations, as well as the chimeric immunoglobulin/T cell receptor construction are the major topics of this review.
Antibodies, Monoclonal↗