Abstract 3661: Vascular changes and potentiating secondary drug delivery in colorectal cancer with Irinophore C

Abstract

Abstract Introduction: Colorectal cancer is the third most common cancer in the world. The predominant chemotherapeutic treatment in CRC is a combination of 5-fluorouracil (5-FU) and irinotecan (CPT-11). However, the combination is limited by toxicity and resistance. We now report on the effects of 5-FU in combination with a liposomal formulation of CPT-11, Irinophore C, that is more efficacious and less toxic than free CPT-11. Materials and Methods: 5-FU was used singly and in combination with Irinophore C in a subcutaneous model of colorectal cancer, HT-29, to assess therapeutic efficacy and toxic effects. 5-FU and Irinophore C (40mg/kg) were injected intravenously on a Q7Dx3 schedule, and tumor growth delay was measured. In a subsequent study, a single bolus injection of 14C-spiked 5-FU was delivered at different timepoints during Irinophore C (tritium-labeled) or saline treatment (Q7Dx3), and the accumulation of 5-FU in tumor tissue measured with scintigraphy. Tumors were also harvested and snap-frozen at early (days 1 - 7) and late (days 14 and 21) time points following Irinophore C treatment. Cryosections were subsequently examined for perfusion using the fluorescent dye Hoechst 33342, stained for apoptosis (TUNEL), CD31, CD105, Collagen IV and with H&E to examine changes in vascular function and tissue morphology. Results: Irinophore C significantly reduced tumour growth (p<0.001) with little or no toxicity compared to saline controls, 5-FU alone and free CPT-11 plus 5-FU. In some cases, tumour growth was completely abolished. When used in combination with 5-FU, there was a slight increase in growth delay. Treatment of the tumours with Irinophore C increased the accumulation of the active lactone form of the drug in the tumour, and also significantly increased the tissue accumulation of a single bolus injection of 5-FU after two (∼50% increase, p<0.001) and three weeks (∼66% increase, p<0.001). Following treatment with Irinophore C, the density of tumor tissue was decreased, and the vascular coverage was increased, leading to increased total perfusion. In addition, apoptotic activity was increased following 1 to 2 weeks of treatment with Irinophore C, compared to controls. Conclusions: Irinophore C is more efficacious, and less toxic, than free CPT-11. This novel formulation of CPT-11 appears to have a bimodal mechanism of action wherein both endothelial and cancer cells are targeted, and which may improve the delivery of a second drug. We further believe that the dose of Irinophore C used in the combination studies is with 5-FU is overly efficacious and masks the effects of 5-FU. Clinically, Irinophore C with its low toxicity and high efficacy could have advantages over the use of free CPT-11. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3661.