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Synthesis and mechanism of action of novel classes of retinoids and rexinoids with antineoplastic activities

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Towards effective therapy for mantle cell lymphoma

Members of the project consortium ANTICANCER RETINOIDS have investigated the action of retinoic acid against mantle cell lymphoma at molecular level.

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Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma that initially responds to certain types of high-level chemotherapy but then goes on to progress with a poor prognosis for the patient. However, one possible therapy involves the use of retinoic acid which has been shown to inhibit primary MCL cell cultures as well as established cell lines. The overall objective of the European project ANTICANCER RETINOIDS was to research the effectiveness of retinoids as potential drug therapies against a range of cancers. Project partners at Centro di Riferimento Oncologico di Aviano in Italy made MCL the target of their research. In particular, they aimed to outline the pathways involved in retinoid action. The team found that certain genes were upregulated and some were inhibited as a result of retinoid action. The scientists also noted that retinoic acid (RA) acted either on its own accord to prevent further differentiation of cancer cells or in conjunction with other anti-cancer agents. Autonomous action included upregulation of a protein that binds to complexes leading to the inhibition of cyclin-dependent kinase 4 (CDK4) activity. This enzyme is required to maintain and initiate tumours. Treatment with RA also decreases the levels of phosphorylated (active) Akt which is involved in cellular survival pathways. By contrast, in conjunction with retinoid X receptor (RXR), retinoic acid receptors (RARs) mediate MCL cell growth inhibition. The anti-viral compound interferon-A (IFN-A) increases the antiproliferative influence of RA on MCL cells. Moreover, one isomer of retinoic acid, 9-cis-RA induced apoptosis, namely programmed cell death, when combined with interferon-A. On the basis of the information gathered, particularly that of the synergistic action with interferon-A, clinical investigations were planned to further assess efficacy for pharmacological development.

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