Succinyl-ß-Ala-Leu-Ala-Leu-Doxorubicine, prodrogue de la Doxorubicine activée sélectivement dans l'environnement immédiat de la tumeur : pharmacocinétique, toxicité et efficacité in vivo
(2003)
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- Trouet, André
- Abstract
- In the fight against cancer, the efficacy of chemotherapeutic agents is mainly limited by their lack of selectivity towards cancer cells and the resulting side-effects. One of the major aims of oncology research is to develop more specific drugs of tumor cells. A promising approach is the prodrug strategy. Prodrugs can be defined as pharmacologically inactive agents that are transformed after administration, either by metabolism or by chemical or biochemical breakdown, to generate the pharmacologically active entities. The ETAP strategy (Extracellularly Tumor-Activated Prodrug), developed by professor Trouet, is based on the fact that during the metastatic process cancer cells release an abnormally high level of hydrolytic enzymes. They could advantageously be used to activate ETAP prodrugs. Such prodrugs would be mainly activated in tumor tissue, increasing treatment efficacy and reducing its toxicity. The first prodrug of this type, Super-Leu-Doxorubicin or SLD (NH2-b-Ala-Leu-Ala-Leu-Doxorubicine), was developed from Doxorubicin, the most known anthracycline. The preliminary in vitro studies have shown that SLD was stable in human blood and activated by peptidases released by tumor cells. We showed that SLD administered ip was less toxic and more effective than Doxorubicin. However, we found an unexpected, extremely severe acute toxicity when SLD was administered iv. We demonstrated that this results from the interaction between the cationic agregates of SLD formed at physiological pH and the glycosaminoglycans present at the luminal surface of endothelial cells. This interaction is likely responsible for disseminated intravascular blood coagulation and the rapid death of the study animals. The elimination of the positive charges by succinylation abolishes in vivo acute toxicity (observed after iv injection) without changing the in vitro characteristics of this new ETAP prodrug designated CPI-0004Na. We compared toxicity of this new prodrug to that of Doxorubicin. The results showed that, whatever the route (iv vs ip) or the administration schedule (single vs multiple dosing), CPI-0004Na is less toxic than Doxorubicin on the basis of the LD50 values (from 2.7 times in the case of a single iv administration to 16.2 times after a daily iv administration for 5 consecutive days). Subsequently, the efficacy of CPI-0004Na was compared with that of Doxorubicin. It was first compared in homograft models of experimentally induced pulmonary metastases. In these conditions, the prodrug was as efficacious as Doxorubicin in a B16 melanoma model. In a 3LL-H-61 Lewis Lung carcinoma model, our results indicate that Doxorubicin
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Citations
Dasnois, L. (2003). Succinyl-ß-Ala-Leu-Ala-Leu-Doxorubicine, prodrogue de la Doxorubicine activée sélectivement dans l’environnement immédiat de la tumeur : pharmacocinétique, toxicité et efficacité in vivo. https://hdl.handle.net/2078.5/124193