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Annals of Oncology : Official Journal... Dec 2000This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced... (Clinical Trial)
Clinical Trial
BACKGROUND
This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies.
PATIENTS AND METHODS
BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred.
RESULTS
A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements.
CONCLUSIONS
The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biphenyl Compounds; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Organic Chemicals; Phenylbutyrates
PubMed: 11205466
DOI: 10.1023/a:1008347630465 -
American Journal of Veterinary Research Jul 2001To develop an antibody that specifically recognizes collagenase-cleaved type-II collagen in equine articular cartilage.
OBJECTIVE
To develop an antibody that specifically recognizes collagenase-cleaved type-II collagen in equine articular cartilage.
SAMPLE POPULATION
Cartilage specimens from horses euthanatized for problems unrelated to the musculoskeletal system.
PROCEDURE
A peptide was synthesized representing the carboxy- (C-) terminus (neoepitope) of the equine type-II collagen fragment created by mammalian collagenases. This peptide was used to produce a polyclonal antibody, characterized by western analysis for reactivity to native and collagenase-cleaved equine collagens. The antibody was evaluated as an antineoepitope antibody by ELISA, using peptides +/- an amino acid at the C-terminus of the immunizing peptide. Collagen cleavage was assayed from equine articular cartilage cultured with interleukin-1 (IL-1), +/- a synthetic MMP inhibitor, BAY 12-9566. Cartilage specimens from osteoarthritic and nonarthritic joints were compared for antibody staining.
RESULTS
An antibody, 234CEQ, recognized only collagenase-generated 3/4-length fragments of equine type-II collagen. This was a true antineoepitope antibody, as altering the C-terminus of the immunizing peptide significantly decreased competition for binding in an inhibition ELISA. The IL-1-induced release of type-II collagen fragments from articular cartilage was prevented with the MMP inhibitor. Cartilage from an osteoarthritic joint of a horse had increased staining with the 234CEQ antibody, compared with normal articular cartilage.
CONCLUSIONS AND CLINICAL RELEVANCE
We generated an antineoepitope antibody recognizing collagenase-cleaved type-II collagen of horses. This antibody detects increases in type-II collagen cleavage in diseased equine articular cartilage. The 234CEQ antibody has the potential to aid in the early diagnosis of arthritis and to monitor treatment responses.
Topics: Animals; Antibodies; Antineoplastic Agents; Biphenyl Compounds; Blotting, Western; Cartilage, Articular; Collagen Type II; Collagenases; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Horse Diseases; Horses; Immunohistochemistry; Matrix Metalloproteinase 3; Organic Chemicals; Osteoarthritis; Peptide Fragments; Phenylbutyrates; Proteoglycans; Rabbits
PubMed: 11453476
DOI: 10.2460/ajvr.2001.62.1031