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Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin.
- Source :
-
British journal of cancer [Br J Cancer] 1999 Feb; Vol. 79 (5-6), pp. 882-7. - Publication Year :
- 1999
-
Abstract
- We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.
- Subjects :
- Adult
Aged
Alanine Transaminase blood
Alkenes adverse effects
Alkenes pharmacokinetics
Alkenes toxicity
Antibiotics, Antineoplastic toxicity
Aspartate Aminotransferases blood
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Small Cell
Colorectal Neoplasms drug therapy
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Female
Half-Life
Humans
Lung Neoplasms drug therapy
Male
Metabolic Clearance Rate
Middle Aged
Neoplasms blood
Polyenes
Pyrones
Teniposide toxicity
Topoisomerase II Inhibitors
Tumor Cells, Cultured
Antibiotics, Antineoplastic adverse effects
Antibiotics, Antineoplastic pharmacokinetics
Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0007-0920
- Volume :
- 79
- Issue :
- 5-6
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 10070885
- Full Text :
- https://doi.org/10.1038/sj.bjc.6690141