Abstract
The ability of a panel of camptothecin derivatives to access the tumor compartment was evaluated to determine the mechanisms by which the architecture of solid tumors may act to limit their activity. Microregional localization and activity of members of the camptothecin class of topoisomerase I targeting agents, including topotecan, irinotecan, and irinophore C, a lipid-based nanoparticulate formulation of irinotecan, were evaluated over time in HCT116 and HT29 colorectal tumor xenografts. Using native drug fluorescence, their distributions in tissue cryosections were related to the underlying tumor vasculature, tumor cell proliferation, and apoptosis. Topotecan exhibited a relatively uniform tumor distribution; in tissue 100 μm away from vessels, it reached 94% ± 5% of levels seen around blood vessels, whereas irinotecan and irinophore C were found to reach only 41% ± 10% and 5% ± 2%, respectively. Surprisingly, all three agents were able to initially inhibit proliferation uniformly throughout the tumors, and it was their rate of washout (topotecan > irinotecan > irinophore C) that correlated with activity. To explain this discrepancy, we looked at SN38, the active metabolite of irinotecan, and found it to penetrate tissue similarly to topotecan. Hence, the poor access to the tumor compartment of irinotecan and irinophore C could be offset by their systemic conversion to SN38. It was concluded that all three agents were effective at reaching tumor cells, and that despite the poor access to the extravascular compartment of irinophore C, its extended plasma exposure and systemic conversion to the diffusible metabolite SN38 enabled it to effectively target solid tumors.
Highlights
The natural compound camptothecin and its synthetic analogues represent a chemically diverse class of biologically active topoisomerase targeting agents with differing physicochemical properties and clinical applications [1,2,3,4]
Large disparity observed in microregional distribution of camptothecins in solid tumors Figure 1 shows the typical pattern of drug fluorescence observed in HCT116 xenografts at 1 hour following treatment with topotecan (10 mg/kg i.p.), irinotecan (50 mg/kg i.v.), and irinophore C (50 mg/kg i.v.), reflecting typical doses used for the agents [6, 18]
In the HCT116 xenografts, irinotecan and irinophore C permeable vessels seemed to be randomly distributed throughout the tumor, whereas in the HT29 xenografts, the drug-permeable www.aacrjournals.org
Summary
The natural compound camptothecin and its synthetic analogues represent a chemically diverse class of biologically active topoisomerase targeting agents with differing physicochemical properties and clinical applications [1,2,3,4]. Two clinically approved analogues exist, topotecan and irinotecan, while there are currently efforts being made to develop a new generation of compounds that exhibit significantly longer systemic exposures [5,6,7,8]. To understand the mechanisms limiting the biologic activity of these agents, and to test the fundamentals driving the development of the new generation of compounds, we have applied a tumor mapping technique to evaluate both the microregional activity and localization of a panel of camptothecin analogues. Factors affecting the delivery and distribution of drugs in tumors span a diverse set of mechanisms, including drug pharmacokinetics as well as tumor vessel functionality, access the tumor cell compartment, uptake, and metabolism by cells [9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
