Apoptosis stimulators have emerged as key targets for the control of cancer. This therapeutic class has, however, remained predominantly experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. These issues are being addressed as our understanding of the field evolves, and as a result, the identification and exploitation of new targets remains a considerable focus of attention - indeed the number of pro-apoptotic molecules in preclinical development has risen by about 10-fold since 1995.

From a molecular point of view this field has concentrated heavily on the caspases and endogenous inhibitors of apoptosis, predominantly Bcl-2 proteins. Over the past few years a considerable amount of research has been conducted and our view of apoptosis has changed dramatically. Major advances have included the emergence of the IAP ("Inhibitor of Apoptosis Proteins") family.

Disruption of the apoptotic pathways may account for resistance to chemotherapy and treatment failures in human neoplastic disease. Such treatment failure is well exemplified by acute myeloid leukemia (AML). This cancer is responsive to both cytotoxic drugs that act through the stimulation of apoptosis as well as differentiating therapies. Unfortunately however, remission is frequently only transient and new approaches are therefore required.

KRN5500, a derivative of spicamycin, is being developed by Kirin Brewery as an anti-cancer treatment. It is currently in Phase I trials in colon cancer in the US. A report from 2000 described the proapoptotic and differentiating activity of KRN5500 against APL cell lines and in cells isolated from children with acute leukemia. Apoptosis induced by KRN5500 was associated with down-regulation of Bcl-2 expression.

Chronic lymphocytic leukemia (CLL) has a similar incidence to that of AML. Although 5-year survival is approximately 60%, and therefore better than that of AML, treatment with conventional doses of chemotherapy is nonetheless palliative and once again new treatment option are required. The effect of KRN5500 on peripheral mononuclear cells from CLL patients has also been recently investigated. KRN5500 reduced the viability of the cells with sub-micromolar efficacy, due to the activation of the intrinsic caspase cascade (caspase-9) and caspase 3 effector caspase. Differing from the situation with AML however, KRN5500 failed to alter the expression of the anti-apoptotic mitochondrial membrane protein Bcl-2. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL as well as those with AML.

Entry date March, 2003

Adapted from Byrd et al, Blood 2003 Feb 20 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk