Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

Abstract

SummaryWe 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.Keywords: fostriecin; topoisomerase II; phase I; pharmacokinetics 882British Journal of Cancer (1999) 79(5/6), 882-887 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received prior chemo-, immuno-or radiotherapy for at least 4 weeks before study entry; white blood cell (WBC) count ≥ 4000 µl -1 and platelet count ≥ 100 000 µl -1 ; bilirubin ≤ 25 µmol l -1 and aspartate-amino transferase (AST) and alanine-amino transferase (ALT) within 2.5 times the normal upper limit; normal prothrombin time (PT); creatinine clearance ≥ 60 ml min -1 . Written informed consent was obtained from all patients. The protocol was approved by the Medical Ethical Committee of the University Hospital Groningen.Fostriecin was supplied by NCI (Bethesda, MD, USA) as a lyophilized powder and was diluted with 0.9% NaCl to 50 or 100 ml. It was administered as a 60-min intravenous (IV) infusion through an UV-light protected system on days 1-5 at 4-week intervals. The dose was initially escalated according to the Fibonacci scheme, with subsequent dose steps of 2, 4, 6.6, 10 and 12.2 mg m -2 day -1 and thereafter increased to 20 mg m -2 (the protocol was amended during the study to allow more rapid dose escalation). Three patients were entered at each dose level, with a maximum of three additional patients when one out of three experienced dose-limiting toxicity (DLT). When no DLT was observed, ...

Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster

“…These observations unequivocally demonstrate that the plmS 2 gene product is responsible for catalyzing hydroxylation at C-18 of PLM and is not required for hydroxylation at other positions. Hydroxylation at C-8 and the C-8 ethyl side chain are most likely catalyzed by the second cytochrome P-450 monooxygenase, encoded by plmT 4 . The efficient production of PLM-B by the NP1 strain suggests that hydroxylation at C-18 of PLM-B and the subsequent esterification step may be the final steps in the biosynthetic process.…”

“…2 -Analysis of the PLM biosynthetic gene cluster, together with the results of the biosynthetic incorporation study, indicated that three hydroxylation steps (C-18, C-8, and the C-8 ethyl side chain) occur after assembly of the polyketide chain from the CHC-derived starter unit. Analysis of the PLM biosynthetic gene cluster revealed two ORFs, plmT 4 and plmS 2 , that both encode proteins with high sequence similarity to each other (38% identity and 53% similarity) as well as cytochrome P-450 monooxygenases from several microorganisms, including those involved in the modification of the natural products of streptomycetes (41). We reasoned that replacement of one of these genes would provide a strain blocked in hydroxylation of C-18 of PLM.…”

“…Phase I clinical trials of fostriecin were suspended before either dose-limiting toxicities or therapeutic plasma levels were attained because of inherent drug instability and unpredictable purity in the clinical supply of the natural product (1,4). In an attempt to address these limitations and further develop this class of novel antitumor agents, no less than six elegant total syntheses of fostriecin have been developed over a short 2-year period (5,(17)(18)(19)(20)(21).…”

Design, Synthesis and Anti-proliferative Activity of Novel 5,6-Dihydro-6-alkyl-2-pyrone Analogues

“…曲 星 (Fostriecin) [1,2] 、 哥 纳 香 甲 素 (Goniothalamin) [3] 、 Cytostatin [2] 、Leptomicin B [4] 、Anguinomycin [2] 、Piro- Micheal 加成, 形成共价键 [4,8] , 在发挥作用的同时, 也 …”

Development and Validation of a Robust and Sensitive Assay for the Discovery of Selective Inhibitors for Serine/Threonine Protein Phosphatases PP1α (PPP1C) and PP5 (PPP5C)

“…8 Fostriecin demonstrated sufficient antitumor activity in animals to warrant Phase I human clinical trials. 9,10 The other afore-mentioned natural products are strong inhibitors (IC 50 ; low nM) of PP1/PP2A/PP4/PP5/PP6 that demonstrate modest or no selectivity. They have some utility as research reagents, but the combined inhibition of PP1-PP6 is toxic to most, if not all, eukaryotic cells.…”