ABSTRACT
Melanoma tumor growth and progression are highly dependent on adequate blood supply through angiogenesis. Since several genes involved in angiogenesis revealed potential binding sites for the transcription factor Sp1, we have examined the effects of local inoculation of Sp1 decoy oligodeoxynucleotides (ODNs) on the growth of transplanted murine melanoma tumors and the expression of VEGF and TNF-alpha within these tumors. Treatment with Sp1 decoy ODNs, but not their mutated form, led to a significant increase (P=0.041) of the tumor necrotic area, as evaluated morphometrically. Tumor necrosis was associated with a significant decrease of microvascular density (P=0.012) and relative vascular area (P=0.026), as determined by counting CD34-positive vascular structures within the tumor microenvironment of Sp1 decoy ODNs and control ODN-treated tumors. RT-PCR experiments showed a strong decrease in the levels of VEGF188 and VEGF164 isoforms and a moderate decrease of TNF-alpha in Sp1 decoy-treated tumors. Taken together, our results indicate that Sp1 decoy ODNs may inhibit angiogenesis by affecting the gene expression of key players in angiogenesis such as TNF-alpha and VEGF. These findings indicate that Sp1 decoy ODNs may be a potential new therapeutic tool in antiangiogenic therapy.
Subject(s)
Genetic Therapy/methods , Melanoma/therapy , Neovascularization, Pathologic/therapy , Oligodeoxyribonucleotides, Antisense/administration & dosage , Skin Neoplasms/therapy , Sp1 Transcription Factor/genetics , Animals , Gene Expression Regulation , Melanoma/metabolism , Melanoma/pathology , Mice , Mice, Inbred C57BL , Necrosis , Neoplasm Transplantation , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Tumor Necrosis Factor-alpha/genetics , Vascular Endothelial Growth Factor A/geneticsABSTRACT
In the course of our screening program to discover antimalarial antibiotics, which are active against drug resistant Plasmodium falciparum in vitro and rodents infected with P. berghei in vivo, from the culture broth of microorganisms, we found a selective and potent active substance produced by an actinomycete strain K99-0413. It was identified as a known polyether antibiotic, X-206. We also compared the in vitro antimalarial activities and cytotoxicities of 12 known polyethers with X-206. Among them, X-206 showed the most selective and potent inhibitory effect against both drug resistant and sensitive strains of P. falciparum. Comparison of biological activities and ion-affinities of the above antibiotics suggests that monovalent cations play an important biological role for the intracellular growth of P. falciparum in parasitized erythrocytes. Moreover, X-206 showed potent in vivo antimalarial activity on the rodent model, though the therapeutic window was narrow compared with its selective toxicity in vitro. These observations are the first report of antimalarial activity of X-206.
Subject(s)
Actinomycetales/metabolism , Anti-Bacterial Agents , Anti-Bacterial Agents/pharmacology , Antimalarials/pharmacology , Artemisinins , Ethers, Cyclic , Ethers, Cyclic/pharmacology , Animals , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/therapeutic use , Antimalarials/isolation & purification , Antimalarials/therapeutic use , Artemether , Artesunate , Cell Death/drug effects , Cell Line , Chloroquine/pharmacology , Drug Resistance , Embryo, Mammalian , Embryo, Nonmammalian , Ethers, Cyclic/isolation & purification , Ethers, Cyclic/therapeutic use , Humans , Malaria/drug therapy , Mice , Molecular Structure , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Quinine/pharmacology , Sesquiterpenes/therapeutic useABSTRACT
BACKGROUND: In the present study, we investigated the effect of dexamethasone (DEX) therapy on extubation and pulmonary function in patients with chronic lung disease (CLD) who required long-term mechanical ventilation. In addition, we compared the effects of DEX therapy among CLD types. METHODS: Twenty-two CLD patients who were ventilator dependent for 28 days or longer received DEX therapy for the purposes of extubation. A tapering dose of DEX, starting from 0.5 mg/kg per day, was administered for 7 days. Pulmonary function was measured at initiation of administration and 4 days after initiation. We evaluated static respiratory system compliance (Crs) and static respiratory system resistance (Rrs) adjusted by bodyweight. Chronic lung disease types were categorized according to the classification of the Ministry of Health and Welfare Research Project. We compared the effect of DEX therapy among CLD types. RESULTS: Dexamethasone therapy was started at a mean (+/-SD) 45 =/- 11 days after birth and 32.1 +/- 1.3 weeks of postconceptional age in infants with a mean bodyweight of 939 +/- 153 g. After DEX therapy, extubation was successful in all 22 patients. Following DEX administration, Crs was significantly increased from 0.69 +/- 0.13 to 1.17 +/- 0.21 mL/cm H2O per kg. In contrast, Rrs did not show any clear changes. Comparing CLD types, no difference was observed for Crs and Rrs in each disease type. CONCLUSIONS: Dexamethasone was administered to CLD patients requiring long-term mechanical ventilation for the purposes of extubation and extubation was successful in all patients. It was found that Crs was increased in all patients following DEX, regardless of CLD type. The increase in Crs following DEX administration may have been related to successful extubation.
