Yehuda Shoenfeld, MD, Yaniv Dhemer, MD, Yaakov George, MD and Dror Harats, MD
Zvi R. Cohen, MD, Revital Duvdevani, PhD, Dvora Nass, MD, Moshe Hadani, MD and Zvi Ram, MD
Background: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense preclinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothetial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer.
Objective: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature.
Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir). was evaluated.
Results: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.
Conclusion: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.
Shaul Sukenik, MD, Ron Baradin, MD, Shlomi Codish, MD, Lily Neumann, PhD, Daniel Flusser, MD, Mahmoud Abu-Shakra, MD and Dan Buskila, MD
Background: Balneotherapy has been successfully used to treat various rheumatic diseases, but has only recently been evaluated for the treatment of fibromyalgia. Since no effective treatment exists for this common rheumatic disease, complementary methods of treatment have been attempted.
Objectives:To assess the effectiveness of batneotherapy at the Dead Sea area in the treatment of patients suffering from both fibromyalgia and psoriatic arthritis.
Methods: Twenty-eight patients with psoriatic arthritis and fibromyalgia were treated with various modalities of batneotherapy at the Dead Sea area. Clinical indices assessed were duration of morning stiffness, number of active joints, a point count of 18 fibrositic tender points, and determination of the threshold of tenderness in nine fibrositic and in four control points using a dolorimeter.
Results: The number of active joints was reduced from 18.4+10.9 to 9+8.2 (P< 0.001). The number of tender points was reduced from 12.6+2 to 7.1±5 in men (P<0.003) and from 13.1+2 to 7.5+3.7 in women (P<0.001). A significant improvement was found in dolorimetric threshold readings after the treatment period in women (P< 0.001). No correlation was observed between the reduction in the number of active joints and the reduction in the number of tender points in the same patients (r= 0.2).
Conclusions: Balneotherapy at the Dead Sea area appears to produce a statistically significant substantial improvement in the number of active joints and tender points in both male and female patients with fibromyalgia and psoriatic arthritis. Further research is needed to elucidate the distinction between the benefits of staying at the Dead Sea area without balneotherapy and the effects of balneotherapy in the study population.