The study hypothesized that because adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents, treatment with CA4P would promote leukemic cell death by disrupting leukemic cell cytoskeletal stability and interfering with vascular cell interactions. Low and non-toxic doses of CA4P inhibited leukemic cell proliferation in vitro and induced mitotic arrest and cell death.
Furthermore, CA4P prolonged survival without inducing hematological toxicity, likely by inhibiting proliferation and circulation of leukemic cells, and diminished the extent of peri-vascular leukemic cell infiltrates. These anti-leukemic effects were shown to be mediated by mitochondrial damage and down-regulation of the cell-adhesion protein VCAM-1, without causing hematological toxicities.
Dai Chaplin, head of R&D and chief scientific officer for Oxigene, said: “We are very encouraged by these results seen with Zybrestat, which point to new mechanisms and indicate that its clinical potential could extend beyond solid tumors, where current clinical development efforts are focused, into hematological malignancies. With a greater understanding of Zybrestat’s mechanism of action, Oxigene believes that it is positioned to exploit the full clinical potential of this novel therapeutic candidate.”