Abstract 827: Camptothecins: Tissue penetration and implications for therapy

Abstract

Abstract We have evaluated distribution and micro-regional activity of members of the camptothecin class of topoisomerase I targeting agents including topotecan (TPT), irinotecan (IRN), Irinophore C (IrC), a liposomal formulation of IRN and SN38, the active metabolite of IRN. Despite having a similar mechanism of action these agents are used against different cancers and possess significantly different pharmacological and physicochemical properties. The native fluorescence of each agent was used to visualize its distribution in HCT116 & HT29 tissue cryosections that were subsequently processed via multiplexed staining to relate drug exposure to its effect on tumor cell status (proliferation, apoptosis) and distance from vasculature. TPT exhibited the most uniform tumor distribution but it also experienced a significantly faster tumor wash-out while IRN was retained longer in tumors but exhibited a larger concentration gradient in relation to tumor blood vessels. IrC, the high molecular weight liposomal formulation, exhibited the poorest tissue distribution but it also displayed longer tumor retention due to its extended plasma half-life. At a depth of 100 µm away from vessels drug levels reached 94 ± 5 % (TPT), 41 ± 10 % (IRN) and 4.8 ± 2 % (IrC) of maximal levels seen near vessels. In terms of vessel permeability, IRN and IrC did not extravasate equally from all vessels, ∼50% of vessels showed little permeation by the two drugs and, because of this, some microregions of the tumors received much higher exposure than others. However, despite the significant differences in their tissue distribution, all 3 agents were able to exert a complete suppression of cycling tumor cells at 4 hours following treatment. At 24 hours following TPT or IRN tumor proliferation status returned to normal levels indicating that neither drug was retained long enough to exert activity on out of cycle cells. In contrast IrC benefited from an extended plasma exposure and was able to inhibit proliferation over a period of several days. The time to 50% recovery in proliferation was ∼3 days for TPT and IRN versus 14 days for IrC. Tumor growth delay studies showed that both TPT and IRN benefited somewhat from a dose splitting schedule designed to specifically target proliferation at peak levels two days in row. However, this strategy was still outperformed by IrC. Tumor growth delay following 50 mg/kg drug qwx2 was 9.6 ± 3 days (IRN) versus 27.8 ± 3.8 days (IrC). To determine the root cause of the discrepancy between the poor distribution but good microregional activity of IRN and IrC an in vitro 3D tissue-disc model was employed. It was found that IRN tissue penetration was limited by its high degree of cellular accumulation. SN38, the active metabolite of IRN, did not accumulate to the same extent and did penetrate tissue effectively. Hence it was concluded that the poor tissue distribution observed for both IRN and IrC was offset by systemic conversion to SN38, which was able to exert a more uniform activity within tumors. Citation Format: Alastair H. Kyle, Maria Jose Gandolfo, Jennifer H.E. Baker, Andrew I. Minchinton. Camptothecins: Tissue penetration and implications for therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 827. doi:10.1158/1538-7445.AM2014-827