Distribution of Gemcitabine Is Nearly Homogenous in Two Orthotopic Murine Models of Pancreatic Cancer

Abstract

Pancreatic cancer is one of the leading causes of cancer-related death in the United States. Gemcitabine is a common treatment, but response rates are low, perhaps due in part to tumor hypoxia. We utilized (14)C-labeled gemcitabine to map distribution of the drug with respect to perfused and hypoxic regions of the tumor microenvironment in two orthotopic xenograft models of pancreatic cancer. There was only a slight reduction in gemcitabine in hypoxic areas, with ∼78% of the drug present in hypoxic compared to perfused areas. In addition, only a 4% reduction in gemcitabine was measured at >100 μm from perfused blood vessels. Thus, despite significant areas of hypoxia in these tumors, gemcitabine distribution is relatively homogenous. Ours is the first study to directly measure gemcitabine distribution within tumor tissue, demonstrating that in these models, tumor tissue does not represent a barrier to gemcitabine penetration.

In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2′-deoxy-2′-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models

“…There was little activity found in the bulk tumor regions or hypoxic zones. This is in contrast to previous results with AsPC1 tumors [24] where we found gemcitabine to be more evenly distributed throughout the tumor with significant accumulation in hypoxic tissue. However, AsPC1 tumors grow with very little stroma and this may lead to increased drug accessibility.…”

Lipid metabolism as a target for cancer drug resistance: progress and prospects

“…Thus, overcoming drug resistance has become a critical issue in anticancer therapy. Recent studies have highlighted the role of lipid metabolism in influencing drug resistance (Kramer et al, 2015;Wu et al, 2015;Cotte et al, 2018). It has been shown that lipid-related processes can impact drug efficacy by affecting drug diffusion, altering membrane permeability, influencing mitochondrial function, and modulating the activity of ABC transporter proteins (Hegedüs et al, 2015).…”

“…A recent study demonstrated that LysoPL containing long saturated fatty acyl chains can induce drug resistance. This protective effect of LysoPL enables tumor cells to withstand DNA-damaging agents like cisplatin, representing a lipid-specific and drug-specific protective mechanism (Kramer et al, 2015) (Figure 2).…”

“…Subsequent investigations have revealed that the resistance to chemotherapeutic agents in H35 and HepG2 cells can be reversed by treatment with lovastatin, an inhibitor of HMG-CoA reductase (HMGCR) that inhibits cholesterol resynthesis and prevents cholesterol accumulation in the mitochondrial membrane (Smith and Land, 2012). Moreover, a significant increase in mitochondrial cholesterol content has been observed in liver cancer tissues compared to normal tissues (Kramer et al, 2015). In this context, inhibition of the mevalonate pathway has been shown to reduce mitochondrial cholesterol content and enhance the hepatocyte response to the mitochondria-targeting drug doxorubicin, thereby sensitizing the cancer cells to chemotherapy (Montero et al, 2008).…”

Quantification of fluorophore distribution and therapeutic response in matched in vivo and ex vivo pancreatic cancer model systems

“…A remaining concern is whether the applied therapeutic reaches its intended tumor target, a repercussion of a robust self-defense mechanism that tumor cells and the surrounding microenvironment put forth [8]. Uncoupling these complex tissue-drug interactions have been analyzed in the context of overall drug distribution using radiolabeled therapeutics [9,10], mass spectroscopy tissue analysis [11,12] and computational modeling [13,14], however these tools have limited utility for extensive, patient-specific screening assays to inform personalized therapy. Although fluorescent-based assays have been gaining traction [15], a patient-specific screening assay has yet to be developed.…”