1,721,260 research outputs found
Metronomic Chemotherapy; pharmacology and clinical applications.
No full textThis book analyzes all aspects of metronomic
chemotherapy, a new approach involving
low-dose, long-term, and frequently administered
therapy that has preclinical and clinical
activity in various tumors. After an opening
section on the pharmacological bases
of metronomic chemotherapy, including its
antiangiogenic effects and impact on immunity,
preclinical studies on various classes of
drug are discussed. Clinical applications of
metronomic chemotherapy in a wide variety
of tumors are then addressed in detail, with
description of the results of all published
studies. The clinical pharmacology of metronomic
chemotherapy is also considered in
depth, encompassing pharmacokinetics,
pharmacogenetics, pharmacoeconomics,
and adverse drug reactions. The book closes
by describing the role of this therapy in the
veterinarian clinic
Bevacizumab pharmacogenetics in tumor treatment: still looking for the right pieces of the puzzle
Full text linkThe possible role of chemotherapy in antiangiogenic drug resistance
No full textThe use of antiangiogenic drugs for cancer treatment was welcomed because of the hypothesis that they would be much less likely to lose their therapeutic activity as a result of tumor-acquired resistance over time. Unfortunately, the clinical experience has shown that acquired resistance to antiangiogenic therapeutic strategies is possible since many patients whose tumors initially respond to drugs such as bevacizumab (a monoclonal antibody against VEGF), sorafenib, or sunitinib (tyrosine kinase inhibitors targeting VEGF receptors and PDGF receptors) or metronomic chemotherapy (e.g. low dose cyclophosphamide) become nonresponsive, often within months of therapy initiation. Indeed, the role of associated antineoplastic chemotherapy in antiangiogenic resistance seems to be ignored by the previous studies and the real part played by these drugs has to be written yet. The studies undertaken on antiangiogenic resistance mainly involved mechanisms directly related to the antiangiogenic drugs alone and as such lead one to ask whether the acquired resistance to angiogenesis pathway-targeting might also be mediated by the chemotherapeutic drugs usually associated (at least into the clinic) with these types of drugs. The proposed hypothesis is concerning the possibility that the acquired resistance to antiangiogenic therapy could be actively and heavily modulated by the choice of the associated chemotherapeutic drug. The chemotherapeutic compounds may delay or accelerate the process through the induction, upregulation or downregulation of pro-angiogenic or anti-angiogenic factors or their receptors in the tumor, endothelial and other type of cells of the tumor microenvironment. In conclusion, the consequences of our hypothesis could be promptly translated into the preclinical studies and verified in clinical trials, involving cancer patients resistant to chemotherapy plus antiangiogenic drug schedules
Drug distribution in tumors: mechanisms, role in drug resistance, and methods for modification
No full textDistribution of antineoplastic agents within tumors remains one of the major challenges in cancer chemotherapy because distribution is hampered by several factors related to the drug (its physicochemical characteristics) and to the neoplastic tissue (blood and lymphatic vasculature, cell density, extracellular matrix composition, and interstitium). The inhomogeneous distribution and structure of tumor vasculature lead to large avascular and hypoxic areas with low pH and high interstitial oncotic pressure. In these critical conditions, the gradient of drug concentrations from the vessels to the inner parts of the tumor is not sufficient to promote diffusion of pharmacologic agents. Again, cellular sequestration and binding to extracellular matrix represent further factors that limit drug distribution and reduce tumor sensitivity to chemotherapy. Several strategies have been investigated to circumvent drug resistance. The evaluation of liposomal and nanoparticle formulations and the characterization of newer bioreductive agents and drugs that should normalize tumor vasculature are in progress
Pharmacogenetic labyrinth of neovascular age-related macular degeneration therapy: how to escape and move forward?
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Historical Overview of the "Firing" Liaison between Brain Tumors and Epilepsy
No full textThis review addresses, in a critical historical perspective, the link between seizures and endocranic neoplasms. Folkloric descriptions of epilepsy can be found in writings from ancient cultures. Hippocrates first provided a medical interpretation. In 1770, Tissot published Traite de l'epilepsie, a milestone in epileptology, whereas the 19th century is considered the golden era of epileptic studies. In 1882, the father of modern epileptology, Jackson, in his article Localized Convulsions from Tumour of the Brain, reported a case of a patient affected by typical Jacksonian seizures in the presence of a brain tumor. However, he did not establish a direct correlation between brain tumors and epilepsy, and an explanation for his clinical case was lacking. Before Jackson's article, other authors reported similar cases, but only Gairdner in 1834 published a report suggesting the concept of a direct relationship between epilepsy and a brain tumor. From the beginning until the mid of the 20th century several authors reported seizures attributed to intracranial tumors, and in recent years studies have focused on the pathogenesis of tumor-related seizures. Biochemical and molecular changes in brain tumors and their environment opened unprecedented working hypotheses on epileptogenesis and on treatment of epilepsy associated with brain tumors
Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs
No full textRecent preclinical studies have shown that frequent administration in vivo of low doses of chemotherapeutic drugs ("metronomic" dosing) can affect tumor endothelium and inhibit tumor angiogenesis, reducing significant side effects (e.g., myelosuppression) involving other tissues, even after chronic treatment. This suggests that activated endothelial cells may be more sensitive, or even selectively sensitive, to protracted ("high-time") low-dose chemotherapy compared with other types of normal cells, thus creating a potential therapeutic window. To examine this hypothesis, we assessed the effects of several different chemotherapeutic drugs--namely paclitaxel, 4-hydroperoxycyclophosphamide, BMS-275183 (an oral taxane), doxorubicin, epothilone B (EpoB) and its analogue 5-methylpyridine EpoB--on human microvascular or macrovascular endothelial cells, fibroblasts, and drug-sensitive or multidrug-resistant breast cancer cell lines in cell culture, using both short-term (24 h) versus long-term (144 h), continuous exposures, where drug-containing medium was replaced every 24 h. Whereas little differential and only weak effects were observed using the short-term exposure, a striking trend of comparative vascular endothelial cell hypersensitivity was induced using the continuous long-term exposure protocol. Potent differential growth inhibition effects as well as induction of apoptosis were observed with IC(50) values in the range of 25-143 pM for paclitaxel, BMS-275183, EpoB, and 5-methylpyridine-EpoB. In contrast, the IC(50) values for tumor cells and fibroblasts tested were in the range of 500 pM to >1 nM for these drugs. Similar differential IC(50) values were noted using 4-hydroperoxycyclophosphamide. The results are consistent with the possibility that continuous low-dose therapy with various chemotherapeutic drugs may have a highly selective effect against cycling vascular endothelial cells, and may be relevant to the use of continuous or frequent administration of low doses of certain types of drugs as an optimal way of delivering antiangiogenic therapy
Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data
Full text linkTumor dormancy is the ability of cancer cells to survive in a non-proliferating state. This condition can depend on three main mechanisms: cell cycle arrest (quiescence or cell dormancy), immunosurveillance (immunologic dormancy), or lack of functional blood vessels (angiogenic dormancy). In particular, under angiogenic dormancy, cancer cell proliferation is counterbalanced by apoptosis owing to poor vascularization, impeding tumor mass expansion beyond a microscopic size, with an asymptomatic and non-metastatic state. Tumor vasculogenic or non-angiogenic switch is essential to promote escape from tumor dormancy, leading to tumor mass proliferation and metastasis. In avascular lesions angiogenesis process results blocked from the equilibrium between pro- and anti-angiogenic factors, such as vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1), respectively. The angiogenic switch mainly depends on the disruption of this balance, in favor of pro-angiogenic factors, and on the recruitment of circulating endothelial progenitors (CEPs) that promote the formation of new blood vessels. Metronomic chemotherapy, the regular intake of doses able to sustain low but active concentrations of chemotherapeutic drugs during protracted time periods, is an encouraging therapeutic approach that have shown to upregulate anti-angiogenic factors such as TSP-1 and decline pro-angiogenic factors such as VEGF, suppressing the proangiogenic cells such as CEPs. In this perspective, metronomic chemotherapy may be one of the available therapeutic approaches capable to modulate favorably the angiogenic tumor dormancy, but further research is essential to better define this particular characteristic
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