[Effect of amifostine on reducing acute toxicity of megachemotherapy of tumors in children]. / Vliv amifostinu na redukci akutní toxicity pri protinádorové megachemoterapii detí.

BACKGROUND: Amifostine (WR-2721, Ethyol) is a chemoprotective agent. There is little experiences with amifostine application in megachemotherapy in children. We evaluated amifostine effect on the reduction of the acute toxicity. METHODS AND RESULTS: Retrospective comparison of patients who received amifostine with the control group (72 vs. 72). Amifostine 750 mg/m2 was given 15 minute before cytostatic dose and regularly each eight hours if we administered cytostatics continuously. Megachemotherapy schedule included melfalan, carboplatin, cyklophosphamid, vepesid, busulfan, thiotepa and karmustin. Type of graft: peripheral stem cells 56 vs. 29, bone marrow 8 vs. 30, combination 8 vs. 13. Nonhematological toxicity: mucositis p = 0.047, hepatotoxicity p < 0.001, nephrotoxicity p = 0.005. Hematological toxicity: engraftment D + 12 vs. D + 15 (p < 0.001), amount of erythrocyte transfusions 3 vs. 6 (p < 0.001), platelet transfusions 7 vs. 9 (p = 0.06), days when number of platelets reaches 20,000 without substitution D + 15 vs. D + 22 (p < 0.001). The only statistically difference was in the in total amount of platelets (p = 0.032), when we calculated patients, who received peripheral stem cells. Number of hospitalization days 14 vs. 18 (p = 0.016), days with antibiotics 14 vs. 18 (p = 0.016), number of febrile days 6 vs. 7 (p = 0.51). CONCLUSIONS: Amifostine reduces mucosal, liver and kidney damage. The graft type could affect hematological results.

Recombinant adenovirus vectors for cytokine gene therapy in mice.

BACKGROUND: Adenoviruses have several specific features useful for gene therapy. They infect various lineages of cells irrespective of cell cycle status. However, the exact mechanism of their infection and in vivo kinetics as a gene expression vector have not been elucidated. OBJECTIVE: Using adenovirus vectors expressing marker genes, we examined the infectivity of these vectors (including cellular and tissue tropism), the duration and intensity of transgene expression, and the side effects. METHODS: Various cells were infected with adenovirus expressing LacZ gene at various doses, and beta-galactosidase activity was measured and compared in relation with dose, time course, and cellular vitronectin receptor. Mice were injected with adenoviruses expressing LacZ, luciferase and GM-CSF, and in vivo gene expression was examined. RESULTS: Adenovirus infection induced viral dose-dependent transgene expression that persisted for 2 weeks. Adherent cells were infected much more efficiently than nonadherent cells, probably because the former expressed much higher levels of the vitronectin receptor, one of the main receptors for adenovirus. Studies performed in mice with luciferase-expressing adenovirus revealed that the liver was the main target organ after intravenous injection and showed that the intravenous route was superior to other routes with regard to transgene expression. After intravenous injection of adenovirus expressing human GM-CSF, there was a transient and dose-dependent increase in the serum level of this cytokine. Administration of adenovirus expressing mouse GM-CSF enhanced hematopoiesis in the spleen and bone marrow. CONCLUSION: These results indicated that adenoviruses can be used for in vivo cytokine gene therapy but suggested the necessity of taking into consideration the route of administration, the duration of transgene expression, the toxic dose, and host immune reactions.