EVALUATION OF CELLULAR RESPONSE, RESISTANCE AND COMBINATORIAL THERAPY WITH VINCRISTINE IN ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Abstract

Vincristine is a powerful, non-myelosuppressive anti-mitotic agent that is particularly effective in the treatment of acute lymphoblastic leukemia (ALL). This important chemotherapy is extensively used together with glucocorticoids like prednisolone as part of multi-agent chemotherapeutic regimens including our Malaysia-Singapore ALL 2010 treatment protocol.

Despite the steady improvements in treatment outcome, around 20% of children still succumb to the malignancy predominantly due to drug resistance or relapse, hindering further progress in the treatment of ALL.

To maximize vincristine’s therapeutic value, vincristine-resistant cell lines and mesenchymal cell co-culture were used as models of vincristine resistance to comprehend cellular mechanisms behind response to vincristine and to explore strategies that aid in overcoming resistance. This study provides evidence that vincristine resistance can be attributed to the expression of the drug efflux transporter MDR1 and the activation of STAT3 signaling. Most importantly, resistance could be attenuated upon combination therapy with prednisolone or signaling pathway inhibitors.