Microregional effects of gemcitabine in HCT-116 xenografts

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 18; pp. 6537 - 6541
• Main Authors: HUXHAM, Lynsey A, KYLE, Alastair H, BAKER, Jennifer H. E, NYKILCHUK, Lani K, MINCHINTON, Andrew I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-09-2004
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacokinetics; Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Colorectal Neoplasms - blood supply; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacokinetics; Deoxycytidine - pharmacology; Female; HCT116 Cells; Humans; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Pharmacology. Drug treatments; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Antimetabolic; Gemcitabine; Fluorine Organic compounds; Heterograft; Heterotransplantation; Pyrimidine nucleoside
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0986

To examine the tumor microregional effects after gemcitabine administration to mice, we mapped the location of proliferating and hypoxic cells relative to vasculature in human colon cancer xenografts. The S-phase marker bromodeoxyuridine was used as a surrogate of drug effect and administered 2 hours before tumor excision, whereas vessel position and perfusion were assessed via staining for CD31 and intravenous injection of carbocyanine, respectively. Hypoxia was detected using pimonidazole. Images of the four markers were overlaid to reveal the spatial relationship between proliferation, vasculature, and hypoxia and to examine the microregional effects. Within 1 day after administration of 240 mg/kg of gemcitabine, proliferation throughout the tumor was completely inhibited. Over time, a reemergence of dividing cells occurred in relation to the distance from vasculature. Microregional analysis revealed that cells located distal to vasculature commenced cycling sooner than cells located proximal to vasculature. A similar trend was seen after multiple doses of gemcitabine (40 mg/kg on days 1, 4, 7, and 10). The possibility that the effect of gemcitabine could be attributed to changes in oxygenation was discounted after examining the vessel perfusion and patterns of hypoxia. The effect of gemcitabine was examined in multilayered cell culture, and at doses <30 micromol/L, a gradient in proliferation between the exposed and unexposed sides was observed. We show a differential effect on cell proliferation in relation to vasculature and conclude that cells distal to blood vessels are less affected by gemcitabine probably because of limited penetration.