aprinocarsen and Fever

Antisense oligonucleotides offer the promise of therapeutic effect with few toxic effects, by virtue of their high selectivity. Preclinical studies have provided evidence of antisense effects in vitro and in vivo, and phase I clinical trials have demonstrated safety, feasibility and activity of antisense oligonucleotides for the treatment of cancer. This review summarizes the status of development of three anticancer antisense oligonucleotides from ISIS Pharmaceuticals.

Topics: Animals; Blood Coagulation Disorders; Clinical Trials, Phase I as Topic; Complement Pathway, Alternative; Drug Administration Schedule; Drug Design; Drug Interactions; Fatigue; Feasibility Studies; Female; Fever; Forecasting; Genes, ras; Genetic Therapy; Humans; Isoenzymes; Liver; Macaca fascicularis; Male; Mice; Neoplasm Proteins; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Partial Thromboplastin Time; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Safety; Thionucleotides; Thrombocytopenia; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The purpose of this study was to assess the efficacy and safety of ISIS 3521, an antisense phosphorothioate oligonucleotide to protein kinase C alpha in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL).. Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle.. The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage III/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and thrombocytopenia (26.9%).. ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted.

Topics: Adult; Aged; Female; Fever; Headache; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Nausea; Neoplasm Staging; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides; Treatment Outcome