Improving drug penetration in tumors by targeting tumor vascularization

Clinical oncologists have not been paying enough attention to the fact that poor tumor penetration represents a major impediment to the efficiency of cancer chemotherapeutics. The cytokine tumor necrosis factor (TNF) was the first treatment shown to affect tumor vessel destruction and improve vascular permeability of drugs in a clinical setting. TNF produces an early increase of vessel permeability followed by a dual targeting: TNF induces apoptosis of intratumoral angiogenic endothelial cells and melphalan during the apoptosis of tumor cells. Given the systemic toxicity, TNF has to be administered by regional therapy. However, experimental data indicate that a systemic approach will be possible, thanks to TNF targeting. Three fusion proteins with TNF were shown to target tumors: anti-EDB fibronectin/TNF, Asn-Gly-Arg-TNF, and anti-gp240/TNF. Current approaches to blocking angiogenesis include strategies that target vascular endothelium growth factor (VEGF)-A. However, little attention has been paid to possible drawbacks, which may include vessel destruction and reduced penetration by chemotherapeutic agents administered simultaneously or subsequently. An antiangiogenic treatment is optimal when it is given at a critical dose and at a critical time. Current protocols seem not to take these prerequisites into consideration. Other new approaches to increased tumor vessel permeability include histamine and combretastatin analog. The current paradigm of antitumor strategy based on the synergism of empirical drug combinations is obsolete. Instead, the design of protocols based on new pharmacodynamic concepts should provide better efficiency of cancer treatment as exemplified in the use of TNF and anti-VEGF antibod

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Purpose: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n=8, and cholangiocarcinoma of the liver, n=1). Experimental design: Gemcitabine at 500, 750 and 1,125mg/m2 was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2′,2′-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20min of stop-flow perfusion, and in peripheral plasma for 420min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH≤7.2, pO2 nadir ratio ≤0.70 or pCO2 peak ratio ≥1.35. The tolerability of this procedure was also assessed. Results: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20min of stop-flow perfusion, with C max levels in the abdominal circuit of 246 (±37%), 2,039 (±77%) and 4,780 (±7.3%)μg/ml for the three dose levels 500, 750 and 1,125mg/m2, respectively. These C max were between 13 (±51%) and 290 (±12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUCt0-20, was between 5.5 (±43%) and 200 (±66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P<0.01 for C max and AUCt0-20, both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P<0.05) was found between systemic C max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions: Regional exposure to gemcitabine—the current standard drug for advanced adenocarcinoma of the pancreas—can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125mg/m2. However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherap

High Frequencies of Naive Melan-a/Mart-1–Specific Cd8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (Hla)-A2 Individuals

Using fluorescent HLA-A*0201 tetramers containing the immunodominant Melan-A/MART-1 (Melan-A) tumor-associated antigen (Ag), we previously observed that metastatic lymph nodes of melanoma patients contain high numbers of Ag-experienced Melan-A–specific cytolytic T lymphocytes (CTLs). In this paper, we enumerated and characterized ex vivo Melan-A–specific cells in peripheral blood samples from both melanoma patients and healthy individuals. High frequencies (≥1 in 2,500 CD8+ T cells) of Melan-A–specific cells were found in 10 out of 13 patients, and, surprisingly, in 6 out of 10 healthy individuals. Virtually all Melan-A–specific cells from 6 out of 6 healthy individuals and from 7 out of 10 patients displayed a naive CD45RAhi/RO− phenotype, whereas variable proportions of Ag-experienced CD45RAlo/RO+ Melan-A–specific cells were observed in the remaining 3 patients. In contrast, ex vivo influenza matrix–specific CTLs from all individuals exhibited a CD45RAlo/RO+ memory phenotype as expected. Ag specificity of tetramer-sorted A2/Melan-A+ cells from healthy individuals was confirmed after mitogen-driven expansion. Likewise, functional limiting dilution analysis and interferon γ ELISPOT assays independently confirmed that most of the Melan-A–specific cells were not Ag experienced. Thus, it appears that high frequencies of naive Melan-A–specific CD8+ T cells can be found in a large proportion of HLA-A*0201+ individuals. Furthermore, as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan-A–specific cells can occur in vivo

Neonatal treatment of giant naevi

SCOPUS: cp.jinfo:eu-repo/semantics/publishe