Inhibiting Tumor Growth by Targeting Tumor Vasculature with Galectin-1 Antagonist Anginex Conjugated to the Cytotoxic Acylfulvene, 6-Hydroxylpropylacylfulvene

Abstract

Targeted delivery of therapeutic drugs promises to become the norm to treat cancer. Here, we conjugated the cytotoxic agent 6-hydroxypropylacylfulvene (HPAF) to anginex, a peptide that targets galectin-1, which is highly expressed in endothelial cells of tumor vessels. In a human ovarian cancer model in mice, the conjugate inhibited tumor growth better than equivalent doses of either compound alone. Immunofluorescence on tumor tissue demonstrated that the conjugate, like parent anginex, selectively targeted tumor vasculature and inhibited tumor angiogenesis. Increased activity from the conjugate further suggests that HPAF retains at least some of its normal cytotoxic activity when linked to anginex. More importantly perhaps is the observation that the conjugate abrogates apparent systemic toxicity from treatment with HPAF. This work contributes to the development of tumor vascular targeting agents against cancer in the clinic.

The Involvement of CD146 and Its Novel Ligand Galectin-1 in Apoptotic Regulation of Endothelial Cells

“…Exogenous Galectin-1 has been previously described to have a biphasic effect on the growth of distinct cell types including endothelial cells. Whereas low concentrations (nanomolar range) induced cell proliferation, high concentrations (micromolar range, equivalent to 20 g/ml) of Galectin-1 seemed to have inhibitory effects (48,(52)(53)(54)(55)(56)(57). Previous studies have shown that endothelial cells secrete Galectin-1 at the ng/ml level upon inflammatory conditions (56).…”

Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression

“…After 7 days, to allow for initiation of angiogenesis in the plugs, anginex-conjugated liposomes with cargo (expression vectors or siRNA) were delivered via intravenous injection. Targeting of the liposomes to the proliferating endothelium was achieved by covalent conjugation of "anginex" peptide (39,40,55) (Phoenix Pharmaceuticals) to the liposome surface. This peptide is bound by galetin-1, which shows increased expression on activated endothelial cells (56).…”

Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer

“…The cells were then exposed to various concentrations of calixarenes for 72 h. Colorimetric assays [CCK-8 (Dojindo; Gaithersburg, MD) and MTT (Sigma; Saint-Quentin Fallavier, France] were used to assess cell viability relative to untreated cells, as described earlier [6, 12, 19, 20]. All measurements were done in triplicate, and the experiments were done at least three times.…”

“…Exponentially growing B16/F10 cells were cultured, harvested, suspended in serum free RPMI (2.0×10 6 cells/mL), and 100 µL was inoculated subcutaneously (s.c.) into the right flank of the mice ( n =10 each group), as described previously [5, 8, 19]. Studies were carried out in a therapeutic intervention model with established tumors to test the capacity of treatment to inhibit tumor growth [6]. Tumors were allowed to grow to the size of approximately 75 mm 3 prior to randomization and initiation of treatment.…”