Abstract 5546: Coupling of hydroxyethyl starch to anticancer drugs for the improvement of tolerability and efficacy.

Abstract

Abstract Background: Standard-of-care anti-cancer drugs exhibit anti-tumor activity but typically display dose limiting toxicities in patients. Poor solubility in water, a short half-life, and a narrow therapeutic window further limit their applicability. The aim of the current studies was to investigate whether coupling of hydroxyethyl starch (HES) to selected anti-cancer drugs with different cleavable linkers improves their efficacy and safety in human tumor xenograft models in mice. Materials and methods: Female NMRI nu/nu mice bearing subcutaneous xenografts of the human large cell lung cancer LXFL 529 were treated twice weekly i.v. for two to four weeks with either the vehicle only, etoposide, temsirolimus or their HES-conjugates. Dosing started at group median tumor volumes of 200-250 mm3. In another model, 5x106 tumor cells from the human breast carcinoma MT-3 cell line were inoculated s.c. followed by i.v. injection of vehicle, docetaxel, or HES-docetaxel conjugates starting on day 7 at palpable tumor size. Docetaxel was administered on 5 consecutive days [5 mg/kg]; the HES-docetaxel conjugates were given only once on day 7 [75 mg/kg]. Moreover, 1x107 cells of the human colon carcinoma HT-29 cell line were implanted s.c. to develop palpable tumors within 8 days. On day 8, the mice received a single i.v. dose of vehicle, irinotecan, or either HES-irinotecan or HES-SN38 conjugates. Tumor volume, body weight, and mortality were monitored during an observation period of up to 90 days. Results: The conjugates were well soluble in saline in contrast to the originator drugs. HES-temsirolimus exerted a higher anti-tumor activity, and HES-etoposide caused a substantially delayed progression of the large cell lung cancer xenograft LXFL 529 after the end of dosing in comparison to the respective originator drug. In the experiment with the breast carcinoma xenograft model, the HES-docetaxel conjugates were better tolerated than docetaxel, allowing the administration of higher doses. HES-docetaxel conjugates exerted a stronger anti-tumor activity compared to the originator drug. In the human colon carcinoma xenograft model, HES-SN38 at the same, or even at a lower dose level compared to irinotecan, caused a substantially stronger tumor growth inhibition dependent on the stability of the linker. Moreover, HES-irinotecan reduced tumor growth to a significantly greater degree than the irinotecan originator. Conclusion: We showed for the first time that the conjugation of HES to drugs is useful to improve their water solubility, making irritating excipients required to dissolve hydrophobic drugs, dispensable. In addition, the coupling of HES to anti-cancer drugs can improve their efficacy and tolerability in tumor xenograft models in mice. The extended release kinetics of HES-drug conjugates may improve the pharmacokinetic profile by reducing exposure peaks, which are typically related to unwanted drug effects. Citation Format: Silke Baasner, Corinna Lupp, Christoph Meyer, Dominik Heckmann, Norbert Zander, Steven Tucker, Martin Westphal. Coupling of hydroxyethyl starch to anticancer drugs for the improvement of tolerability and efficacy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5546. doi:10.1158/1538-7445.AM2013-5546