Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

Original publication




Journal article


Cancer Chemother Pharmacol

Publication Date





395 - 400


Aged, Aminoglycosides, Animals, Anti-Bacterial Agents, Antibiotics, Antineoplastic, Blood Proteins, Carbohydrate Sequence, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Mice, Mice, Inbred BALB C, Middle Aged, Molecular Sequence Data, Neoplasms, Protein Binding, Retrospective Studies, Sensitivity and Specificity