ABSTRACT
The c-myc oncogene has been shown to be overexpressed in a number of malignancies and plays a key role in the abnormal growth regulation of melanoma cells. This study aimed to provide an efficient system for the in vitro manipulation of c-myc expression by antisense oligonucleotides. Therefore, we used poly(NIPA)/PEI2B copolymer as vector in order to improve the intracellular availability and stability of AS ODNs. We targeted oligonucleotide sequences within the human c-myc mRNA as free AS ODNs or conjugated with a thermosensitive copolymer, in an effort to inhibit the growth of human melanoma cells. The conjugates adopted more positive charge and smaller size at 37 degrees C and they had no toxic effects on human fibroblast cells. The conjugated AS ODNs showed increased antiproliferative effect on melanoma cells as compared to free AS ODNs. At a concentration of 100 ng, AS ODNs inhibited SK-MEL 30 human melanoma cell line proliferation maximally by 18.6%, whereas the same amount of conjugated AS ODN provided 52% inhibition. The greatest inhibition was obtained by conjugates having a polymer:AS ODN ratio of 9. Greatest inhibition was detected at 48 h and decreased after 96 h, which may be due to the depletion of AS ODNs. The results confirm the enhanced antiproliferative effects of poly(NIPA)/PEI2B-conjugated AS ODNs, which may provide improved intracellular availability for c-myc-directed antisense strategies.
Subject(s)
Acrylic Resins , Drug Carriers , Melanoma/pathology , Oligonucleotides, Antisense/pharmacology , Polyethyleneimine/analogs & derivatives , Proto-Oncogene Proteins c-myc/genetics , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Melanoma/genetics , Melanoma/metabolism , Melanoma/therapy , Particle Size , Proto-Oncogene Proteins c-myc/biosynthesis , TemperatureABSTRACT
Analgesic and anti-inflammatory effects of N-(p-ethoxyphenyl)-2,6-dihydroxybenzamide (1), N-(p-ethoxyphenyl)-2,6-diacetoxybenzamide (2), N-(p-ethoxyphenyl)-2,5-dihydroxybenzamide (3), and N-(p-ethoxyphenyl)-2,5-diacetoxybenzamide (4) have been investigated in mice and rats. The analgesic effect of 2 on acetic acid-induced writhing was found to be stronger than that of aspirin, whereas that of 1, 3, and 4 was weaker than that of aspirin. In inflammatory studies, 1-4 showed inhibition of formaldehyde-induced paw swelling (edema). The effects of 1-3 were more potent than that of aspirin, 1 being the most potent. The potency of 4 was almost equal to that of aspirin.
