Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. According to the most recent statistics, it was estimated that approximately 1.3 million new cases of cancer would have been diagnosed and 555,500 people would have died from cancer in the United States in 2002. The development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry. Between 1995 and 1998 leukemia was diagnosed in 12 out of every 100,000 American, compared to 66 individuals diagnosed with lung cancers, the most commonly diagnosed types of cancer. Compared with lung cancer, mortality and 5-year survival rates for the leukemias are both favorable although this type of cancer remains a significant clinical problem. In particular the poor prognosis of myeloid leukemias means that 5-year survival rate of all leukemia sufferers is only about 46%. The incidence of tumors within the brain and other nervous system structures is about half that of the leukemias. Of these, glioblastomas are the most common primary brain tumors in adults, accounting for 50-60% of primary brain tumors. Few patients with glioblastomas survive longer than 3 years and only a handful survive 5 years. Therefore improved treatments of both leukemia, particularly myeloid leukemias and glioblastomas are required. The development of apoptosis activators offers a particularly appealing approach to the treatment of cancer in general and this is true for chronic myeloid leukemia and neuroblastoma. Chronic myeloid leukemia is caused by the translocation of the Abelson (abl) tyrosine kinase oncogene of 9q into the 'breakpoint cluster region' (bcr) of chromosome 22 thus forming the Philadelphia chromosome. A similar translocation is also seen in acute lymphocytic leukemia and also Burkitt lymphoma, however chronic myeloid leukemia is characterized by the site of translocation in that bcr is 5-prime to abl. This hybrid gene codes a protein termed p210bcr/abl that has constitutive tyrosine kinase activity due to the activation of abl by bcr. Retroviral infection of healthy bone marrow with p210bcr/abl has been shown to induce a myeloproliferative syndrome closely resembling the chronic phase of human chronic myelogenous leukemia supporting claims that p210bcr/abl contributes to the development of chronic myeloid leukemia. Specifically bcr/abl activates mitogenic and anti-apoptotic pathways conferring resistance against apoptosis induced by many chemotherapeutic agents. Correspondingly AG957 has been developed as an inhibitor of p210bcr/abl tyrosine kinase and has been shown to induce apoptosis in chronic myelogenous leukemia cells. The NIH has discontinued development of AG957, however in a recent publication researchers at the USC in collaboration with the NIH report the activity of NSC 680410, a novel adamantyl ester of AG957. NSC 680410 exhibited antileukemic activity at nanomolar concentrations in various cell lines including those that lack p53, express bcl-2 and VEGF-R1, and thus are refractory to apoptosis. Anti-cancer activity may be due in part to the ability of NSC 680410 to induce apoptosis since caspase-3 cleavage was increased. Furthermore when combined with a VEGF-R1 inhibitor, NSC 680410 was also able to provoke neuroblastoma cell death. This effect was also seen in vivo. These data therefore support further development of NSC 680410 as an approach to difficult to treat leukemias and neuroblastomas.

January, 2003

Adapted from Avramis et al, Cancer Chemother Pharmacol 2002 Dec;50(6):479-89