Treatment of Diffuse-Type Gastric Cancer Cells Using Bi-213-Radioimmunoconjugates In Vitro and In Vivo Following Intraperitoneal Dissemination

Poor prognosis of gastric cancer patients is based on early tumor cell dissemination into the peritoneal cavity. Therefore, efficient therapies for disseminated tumor cells are urgently needed. Patients suffering from diffuse-type gastric cancer occasionally express a mutant variant of E-cadherin lacking exon 9 (d9-E-cad). A monoclonal antibody (d9MAb) labelled with Bi-213 specifically targeting d9-E-cad, therefore is a promising agent for the treatment of disseminated tumor cells. Incubation of HSC45-M2 gastric cancer cells expressing d9-E-cad with Bi-213-d9MAb induced formation of micronuclei and severe chromosomal aberrations finally causing cell death. Since inhibitors of apoptosis could not preserve cells from dying, Bi-213-d9MAb most likely induces necrotic cell death. This has been confirmed by analysis of Bi-213-d9MAb induced expression of genes involved in regulation of cell death. Bi-213-d9MAb treatment arrested HSC45-M2 cells in G2 phase as revealed by BrdU incorporation and by downregulation of genes involved in mitosis and cytokinesis. Therapeutic efficacy of Bi-213-d9MAb was investigated in a nude mouse model following intraperitoneal inoculation of HSC45-M2 cells. Therapy with 1.85 MBq Bi-213-d9MAb on day one after tumor cell inoculation defeated disease in 87% of all cases without any signs of toxicity. Therapeutic efficacy could be visualised non-invasively via bioluminescence imaging. Though higher activities of Bi-213-d9MAb also significantly prolonged survival, they caused long- term kidney toxicity. Therapy at day eight after tumor cell inoculation was less efficient, however fractionated Bi-213-immunotherapy could improve survival. Thus, locoregional radioimmunotherapy with Bi-213-d9MAb is a promising concept for treatment of early peritoneal carcinomatosis caused by intraperitoneal dissemination of gastric cancer cells.