CI-921, an analogue of the antileukaemic agent amsacrine, was produced in an attempt to develop a cytotoxic agent with a broader spectrum of activity. CI-921 was selected for clinical trial on the basis of superior in vivo and in vitro solid tumour activity. Sixteen patients with histologically documented cancer for which there was no conventional cytotoxic treatment were entered into a phase I trial. The dose of CI-921 was escalated from 39mg/m2 to 810mg/m2 (total dose divided over 3 days) and repeated 3 weekly. Neutropenia was the major dose limiting toxicity and defined a maximum tolerated dose of 810 mg/m2. Pharmacokinetic studies revealed a biexponential pattern of drug distribution with a distribution half-life of 2.6 h. The kinetics appeared linear over the dose range tested. Less than 1% of total drug was excreted in the urine. Nineteen patients were entered into a limited phase II trial in non-small cell lung cancer using CI-921 at a dose of 648 mg/m2 in the same 3-day schedule. One of the 16 evaluable patients achieved a partial response lasting five months. Myelosuppression was the predominant toxicity as in the phase I trial, but the degree of toxicity confirmed this dose as being suitable for further phase II trials. One patient had a grand mal seizure temporally associated with three of four courses of CI-927 raising the possibility of neurotoxicity. Although drug-induced cardiotoxicity has been reported with the parent drug amsacrine, there was no evidence of this in the current study. It has been suggested that CI-921 undergoes hepatic metabolism and biliary excretion following conjugation with glutathione. There was no fall in whole blood glutathione levels in patients following CI-921 infusion, although a transient decrease in mouse hepatic GSH was demonstrated following both amsacrine and CI-921. The toxicity of CI-921 in mice was markedly increased following depletion of hepatic glutathione with BSO but was not affected by pre-treatment with morphine or the glutathione "protector" N-acetyl cysteine.
| Identifer | oai:union.ndltd.org:ADTP/275727 |
| Date | January 1989 |
| Creators | Hardy, Janet Rea |
| Publisher | ResearchSpace@Auckland |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
| Rights | Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated., http://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm, Copyright: the author |
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