Inhibition of tumor angiogenesis by hexuronyl hexosaminoglycan sulfate

The efficacy of heparin (HEP), the heparin analogue hexuronyl hexosaminoglycan sulfate (HHS), and hydrocortisone (HC) was studied in inhibiting the growth of four morphologically distinct pancreatic adenocarcinoma lines (CBP, LHP2, LSP3, and Pour-LVG) in hamsters. Animals were inoculated with LD100 doses of one of the four tumor lines and were randomly allocated to groups of five animals, which received in their drinking water either: HEP (1000 U/ml) alone, HHS (10 mg/ml) alone, HC (0.5 mg/ml) alone, HEP plus HC, HHS plus HC, or no additives (control). Tumors were measured, growth rates calculated, and nonparametric statistical comparisons made among the median growth rates of all of the treatment groups. All four tumors were tested in the rabbit cornea assay for their ability to induce angiogenesis. Extracts of tumors from control animals as well as from animals treated with HHS plus HC were prepared for quantitative testing in vitro by endothelial cell migration assay. All four tumor lines caused angiogenesis as measured in the rabbit cornea assay. A reduction in median tumor growth rates was observed in animals treated with HHS plus HC bearing the CBP, Pour-LVG, and LSP3 tumors. Similarly, in vitro capillary endothelial cell migration was decreased by HHS plus HC treatment in animals bearing CBP, Pour-LVG, and LSP3 tumors. Animals bearing the LHP2 tumor showed no effect of HHS plus HC treatment on tumor growth rate and no effect on endothelial cell migration. HEP alone, HHS alone, HC alone, and HEP plus HC showed no effect on tumor growth rate in any of the four tumors tested.