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Updated: Aug 8, 2026
Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
Published on: January 7, 2013
Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with
J Nemunaitis1, J T Holmlund, M Kraynak
1PRN Research, Inc, and Sammons Cancer Center at Baylor, Dallas, TX, USA.
Purpose:
To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha.
Patients And Methods:
Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites.
Results:
Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life.
Conclusion:
No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Insights
ISIS 3521, an antisense oligonucleotide targeting protein kinase C-alpha, showed clinical activity and no dose-limiting toxicity in advanced cancer patients. Further development may require altered dosing schedules due to its short elimination half-life.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- ISIS 3521 is an antisense phosphorothioate oligonucleotide designed to inhibit protein kinase C-alpha.
- Protein kinase C-alpha is implicated in various cancers, making it a potential therapeutic target.
Observation:
- A phase I study evaluated the maximum-tolerated dose (MTD) and pharmacokinetics of ISIS 3521 in 36 advanced cancer patients.
- Patients received ISIS 3521 intravenously at doses ranging from 0.15 to 6.0 mg/kg/d.
- Plasma and urine samples were analyzed to determine drug levels and metabolites.
Findings:
- ISIS 3521 was generally well-tolerated, with mild to moderate toxicities including nausea, vomiting, fever, chills, and fatigue.
- Hematologic toxicity was limited, primarily to thrombocytopenia.
- Two patients with non-Hodgkin's lymphoma achieved complete responses.
- The drug exhibited a short elimination half-life (18-92 minutes) with dose-dependent changes in clearance and exposure.
Implications:
- ISIS 3521 demonstrated clinical activity and an acceptable safety profile, supporting its further investigation.
- The short elimination half-life suggests that alternative administration schedules, such as prolonged infusions, may be necessary to optimize therapeutic efficacy.
- Further clinical trials are warranted to explore the potential of ISIS 3521 in cancer treatment.
