ABSTRACT
A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3'-untranslated region of human protein kinase C-alpha (PKC-alpha) mRNA has been shown to inhibit the expression of PKC-alpha in multiple human cell lines. In human bladder carcinoma (T-24) cells, inhibition of PKC-alpha was both concentration dependent and oligonucleotide sequence specific. ISIS 3521 had a IC50 of 50-100 nM for PKC-alpha mRNA reduction and was without effect on the expression of other members of the PKC family of genes (PKC-eta and zeta). Toxicity studies in mice revealed that the oligodeoxynucleotide was well tolerated at repeat doses of 100 mg/kg i.v. for up to 14 days, with no acute toxicity apparent. The oligodeoxynucleotide was found to also inhibit the growth of three different human tumor cell lines, the T-24 bladder, human lung carcinoma (A549), and Colo 205 colon carcinoma grown in nude mice. The inhibition was dose dependent with ID50 values for the growth inhibition between 0.06 and 0.6 mg/kg daily when given i.v., depending on the cell line examined. Three control phosphorothioate oligodeoxynucleotides not targeting human PKC-alpha were without effect on the growth of the tumors at doses as high as 6 mg/kg. Recovery of ISIS 3521 from tumor tissue and resolution by capillary gel electrophoresis revealed that 24 It after the final dose of oligodeoxynucleotide, intact, full-length 20-mer material was present as well as some apparent exonuclease degradation products (e.g., n-1 and n-2 mers). These studies demonstrate the in vivo antitumor effects of an antisense oligodeoxynucleotide targeting PKC-alpha and suggest that this compound may be of value as a chemotherapeutic agent in the treatment of human cancers.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Isoenzymes/antagonists & inhibitors , Neoplasms/drug therapy , Neoplasms/enzymology , Oligodeoxyribonucleotides, Antisense , Oligonucleotides, Antisense/pharmacology , Protein Kinase C/antagonists & inhibitors , Thionucleotides/pharmacology , Animals , Antineoplastic Agents/toxicity , Base Sequence , Cell Division/drug effects , Female , Humans , Isoenzymes/biosynthesis , Isoenzymes/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Sequence Data , Neoplasm Transplantation , Neoplasms/pathology , Oligonucleotides, Antisense/toxicity , Protein Kinase C/biosynthesis , Protein Kinase C/genetics , Protein Kinase C-alpha , Thionucleotides/toxicity , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Diclofenac is a potent anti-inflammatory and analgesic compound with good antipyretic and uricosuric properties. It is one of the most potent inhibitors of prostaglandin synthetase known. It shows a favourable therapeutic ratio considering its efficacy, and proved superior to the reference drugs in terms of gastro-intestinal tolerability. All metabolites are clearly less potent than the parent compound.
Subject(s)
Diclofenac/pharmacology , Phenylacetates/pharmacology , Analgesics , Animals , Anti-Inflammatory Agents , Anti-Inflammatory Agents, Non-Steroidal , Arthritis, Experimental/drug therapy , Cyclooxygenase Inhibitors , Diclofenac/adverse effects , Diclofenac/metabolism , Dose-Response Relationship, Drug , Drug Tolerance , Humans , Mice , Models, Biological , Rats , Uricosuric AgentsABSTRACT
Diclofenac sodium (Voltaren) is a non-steroid anti-inflammatory agent of a new chemical structure, which is animal experiments shows a high degree of anti inflammatory, analgesic, and antipyretic activity in various pharmacological models. It inhibits prostaglandin biosynthesis in vitro and in vivo, and this inhibitory effect at least partly explains the mechanism of action of the preparation. In animal experiments diclofenac sodium is characterised by a broad therapeutic range. Also, its gastrointestinal tolerability is better than that of other highly effective non-steroid anti-inflammatory agents. Two of the metabolites produced during the biotransformation of diclofenac sodium in man are also biologically active. The activity of these two metabolites, however, is very much weaker than that of unchanged diclofenac sodium and is comparable to that of phenylbutazone.
Subject(s)
Diclofenac/pharmacology , Phenylacetates/pharmacology , Animals , Arthritis, Rheumatoid/drug therapy , Chemical Phenomena , Chemistry , Cyclooxygenase Inhibitors , Diclofenac/metabolism , Diclofenac/therapeutic use , Diclofenac/toxicity , Drug Evaluation, Preclinical , Gastric Mucosa/drug effects , Intestinal Mucosa/drug effects , Lethal Dose 50 , Mice , RatsABSTRACT
The biotransformation of arachidonic acid to prostaglandins in vitro is specifically augmented by endogenous pyrogen to a degree depending on the concentration applied, providing that the microsomal fraction of the cerebral cortex is used as prostaglandin-synthetase system. This effect is inhibited by non-steroidal anti-inflammatory agents. These findings are compatible with the hypothesis that prostaglandins might act as mediators of the febrile reaction induced by endogenous pyrogen.
Subject(s)
Cerebral Cortex/metabolism , Prostaglandins/biosynthesis , Pyrogens/pharmacology , Animals , Arachidonic Acids/metabolism , Cerebral Cortex/drug effects , Diclofenac/pharmacology , In Vitro Techniques , Male , Microsomes/drug effects , Microsomes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Rabbits , Seminal Vesicles/drug effects , Seminal Vesicles/metabolismABSTRACT
A statistically significant correlation can be shown to exist between the concentrations in which established non-steroidal anti-inflammatory agents inhibit prostaglandin synthesis in vitro and the doses in which they exert anti-inflammatory and antipyretic effects in animals. With regard to their antinociceptive activity, this relation is less distinct. Derivatives of clinically effective non-steroidal anti-inflammatory agents can interfere with prostaglandin synthesis in vitro without displaying any activity in vivo. Moreover, the capacity to inhibit this enzyme system is not a property exclusive to non-steroidal anti-inflammatory agents; tricyclic psychotropic drugs exert a similar action. The fact that a substance affects prostaglandin synthetase in vitro is consequently not a reliable indication that it possesses anti-inflammatory properties. On the other hand, the demonstration of effects of this type is important in elucidating the mechanism of action of a drug.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Prostaglandin Antagonists , Prostaglandins/biosynthesis , Analgesia , Animals , Aspirin/pharmacology , Body Temperature/drug effects , Cyclooxygenase Inhibitors , Edema , Flufenamic Acid/pharmacology , Indomethacin/pharmacology , Male , Mefenamic Acid/pharmacology , Oxyphenbutazone/pharmacology , Phenylacetates/pharmacology , Phenylbutazone/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Voltaren, a non-steroid antiinflammatory agent (NSA) of an entirely new chemical structure, is characterized by the high degree of antiinflammatory, antipyretic and analgesic activity it displays in animal experiments. Like other NSAs, the preparation inhibits prostaglandin synthesis, and various findings indicate that the spectrum of pharmacological activity of these agents is at least partly due to this inhibitory effect. Despite this common feature, however, there are quantitative and qualitative differences between Voltaren and other NSAs.
