Ovarian tumor growth regression using a combination of vascular targeting agents anginex or topomimetic 0118 and the chemotherapeutic irofulven

Abstract

Combination of chemotherapeutic agents and angiogenesis inhibitors is now commonly employed in the clinic to treat cancer. Here, we used angiostatic agents anginex and 0118, in combination with the chemotherapeutic irofulven, to treat human ovarian tumor xenografts in mice. General linear mixed models were used to statistically analyze tumor growth curves. Overall, combination of a low, non-toxic dose of irofulven with either angiogenesis inhibitor was more effective at inhibiting tumor growth than any of the single-agent therapies. For example, the anginex/irofulven and 0118/irofulven combinations inhibited tumor growth relative to controls by 92% (p<0.0001) and 96% (p<0.0001), respectively, with the 0118/irofulven combinations yielding 100% complete responses. This study suggests that combination therapy of 0118 or anginex and irofulven may be highly effective in the clinical setting.

Structure-Based Optimization of Angiostatic Agent 6DBF7, an Allosteric Antagonist of Galectin-1

“…LS174T (human prostate adenocarcinoma), MA148 (human ovarian carcinoma), and B16F10 (murine melanoma) were cultured on noncoated flasks using 10% fetal bovine serum and 1% penicillin/streptomycin in RPMI 1640. Cultures were split 1:3 every 3 days (Dings et al, , 2008(Dings et al, , 2011.…”

“…The cells were then exposed to complete medium containing 20 ng/ml of basic fibroblast growth factor (Sigma-Aldrich), with or without various concentrations of anginex, for 72 hours or as indicated otherwise. A cell counting kit (CCK-8; Dojindo, Gaithersburg, MD) was used to assess cell proliferation rates relative to untreated cells, as described earlier (Dings et al, , 2008(Dings et al, , 2011. All measurements were performed in triplicate, and the experiments were conducted at least three times.…”

“…B16F10 cells (2 Â 10 5 ) were inoculated into male C57/BL6 mice, as described previously Dings et al, 2006Dings et al, , 2008Dings et al, , 2011. All mice (5-6 weeks old) were purchased from the National Cancer Institute, except for the female gal-1-null mice, which were purchased from the Jackson Laboratory.…”

“…The diameters of tumors were measured using calipers (Scienceware, Pequannock, NJ), and the volume was calculated using the equation to determine the volume of a spheroid [(a 2  b  p)/6], where a is the width of the tumor and b is the length of the tumor. As an indirect measurement of general toxicity, body weights and hematocrit levels were monitored Dings et al, 2006Dings et al, , 2008Dings et al, , 2011.…”

“…Untreated MA148 tumors were embedded in tissue-freezing medium (Miles Inc., Elkart, IN), snap frozen in liquid nitrogen, and subsequently cut into 5-mm sections. Preparation and procedures for the frozen tumor sections were performed as described earlier, with some slight modifications Dings et al, 2006Dings et al, , 2008Dings et al, , 2011. Briefly, sections were fixed for 10 minutes in acetone.…”