Local delivery of the topoisomerase I inhibitor camptothecin sodium prolongs survival in the rat intracranial 9L gliosarcoma model
✍ Scribed by Jon D. Weingart; Reid C. Thompson; Betty Tyler; O. Michael Colvin; Henry Brem
- Publisher
- John Wiley and Sons
- Year
- 1995
- Tongue
- French
- Weight
- 624 KB
- Volume
- 62
- Category
- Article
- ISSN
- 0020-7136
No coin nor oath required. For personal study only.
✦ Synopsis
Camptothecin, a naturally occurring inhibitor of the DNAreplicating enzyme topoisomerase I, demonstrated promising anti-tumor activity in pre-clinical testing; however, because of unexpected toxicity and low anti-tumor effects in the initial clinical trials, further testing was discontinued. We hypothesized that local controlled delivety of camptothecin sodium would achieve effective concentrations in brain tumors without the observed systemic side effects, thereby allowing this novel drug to be used t o treat patients with malignant gliomas. To test this hypothesis, we evaluated the sensitivity of rat glioma lines and established human glioma lines to camptothecin in vitro. We found that the LDw for the established rat and human lines was 0.3 t o I .4 pM after a I hr exposure and decreased t o less than 0.1 pM after continuous exposure for 7 days. We loaded camptothecin into a controlled-release polymer (ethylene-vinyl acetate co-polymer; EVAc) and showed by highpressure liquid chromatography that controlled release occurred over at least 21 days. We then tested camptothecin against 9L gliosarcoma, implanted into the brain of Fischer 344 rats. Five days after tumor implantation, animals were treated with camptothecin delivered either systemically o r locally by release from EVAc. Local controlled delivery by the polymer significantly extended survival: 59% of the treated animals were long-term survivors (> I20 days) compared to 0% of controls. Systemic administration did not extend survival compared to controls. We compared the efficacy of camptothecin delivered locally with a polymer to camptothecin injected directly into the tumor. Camptothecin increased survival only when delivered locally by polymer.